Treatment Of Kidney Cancer Research Articles

Incorporating New Systemic Therapies in Kidney Cancer Treatment.

In 2017, pazopanib and sunitinib remain the mainstays of frontline therapy for advanced renal cell carcinoma. Independent review of frontline cabozantinib therapy may alter standard of care for patients at intermediate and poor risk. Multiple agents show a survival advantage in the second-line setting, including nivolumab, cabozantinib, and combination lenvatinib and everolimus. Selection of subsequent therapy will depend on patient disease status, comorbidities, and resource availability.

Comorbidity Is a Competing Factor for Disease Recurrence Postnephrectomy.

There is a relation between tumor stage and grade with the risk of cancer recurrence in patients undergoing surgical treatment for kidney cancer. The association of patient comorbidity with disease recurrence is less well characterized. The objective of this study was to explore the association between comorbidity and the recurrence of kidney cancer. We performed a retrospective analysis of 263 patients who received a partial or radical nephrectomy from January 1, 2000 through April 30, 2013. Patient data included race, sex, body mass index, age-adjusted Charlson Comorbidity Index (aaCCI) score, tumor histology, tumor T classification, and Fuhrman grade. The primary outcome was cancer recurrence, either local or distant. Logistic regression was used to assess the association of these risk factors with the outcome. The median follow-up time was 19.6 months (interquartile range 5.2-53.7). There were 101 (38.4%) African American patients and 150 (57.0%) men. The median body mass index was 28.3 and the median aaCCI was 3.0. The Fuhrman grade was G1 in 9.5% of patients, G2 in 45.2%, G3 in 32.8%, and G4 in 12.5%. Nineteen (7.2%) patients experienced disease recurrence, including 13 (4.9%) patients with metastatic disease. The risk factors significantly associated with recurrence included Fuhrman grade (odds ratio [OR] 3.0, 95% confidence interval [CI] 1.23-7.30), tumor T classification (OR 1.33, 95% CI 1.00-1.76), and CCI (OR 0.74, 95% CI 0.57-0.95). Physiologic factors, in addition to tumor characteristics, play a significant role in predicting cancer-specific survival in patients with kidney cancer. The reduced odds of recurrence with higher aaCCI may indicate that competing health factors have an impact before recurrence on survival in certain patients.

Predictive and medicinal singnificance of lymphadenectomy in the surgical treatment of metastatic kidney cancer

Predictive and medicinal singnificance of lymphadenectomy in the surgical treatment of metastatic kidney cancer

Robotic Platform for High-Intensity Focused Ultrasound Surgery Under Ultrasound Tracking: The FUTURA Platform

Focused Ultrasound Therapy Using Robotic Approaches (FUTURA) is a European seventh research framework programme project aimed at creating an innovative platform for Focused Ultrasound Surgery (FUS). Merging robotics together with noninvasive ultrasound monitoring and therapy has the goal to improve flexibility, precision and accuracy of the intervention, thus enabling a large use of FUS for the treatment of different pathologies. The FUTURA platform, based on FUS therapy under US tracking, has been set up with the first clinical target of kidney cancer treatment. Experiments for assessing the accuracy of the FUS delivery with the FUTURA platform have been carried out under in vitro static conditions and presented here as preliminary outcomes of this study.

Current Management Strategy for Metastatic Renal Cell Carcinoma and Future Directions

Major strides have been made in the treatment of kidney cancer in the last several years with checkpoint immunotherapies and novel targeted agents. This manuscript will review current treatment strategies for metastatic renal cell carcinoma and will discuss future directions. Most recently, several new drugs including nivolumab, cabozantinib, and a combination of lenvatinib and everolimus have demonstrated acceptable toxicity and significantly improved overall survival, but evidence-based guidelines for sequencing of the approved treatment options and treatment selection based on biomarkers are still missing. Despite the significant progress, many questions still remain unanswered. Several ongoing clinical trials are evaluating sequencing, timing of cytoreductive nephrectomy, combinations of immunotherapies and targeted therapies as well as selection of the best systemic treatment. Personalized treatment based on tumor profiling is one of the brightest spots on the horizon.

CLINICAL CASE OF SURGERY KIDNEY CANCER WITH TUMOR THROMBUS IN THE ATRIUM AND ISOLATED LIVER METASTASIS

Presents a clinical case of successful surgical treatment of kidney cancer with tumor thrombus of the inferior vena cava (IVC) to the level of the atrium, with simultaneous resection of segment I of the liver containing a single metastasis, in 57-year patient.

641 - Long-term assessment of mortality patterns after surgical treatment for non-metastatic kidney cancer: A competing risk analysis

641 - Long-term assessment of mortality patterns after surgical treatment for non-metastatic kidney cancer: A competing risk analysis

Long term overall survival (OS) in patients with primary metastatic kidney cancer: An analysis of 1468 patients from the Austrian National Cancer Registry (ANCR).

489 Background: The introduction of thyrosinkinase inhibitors (TKI) changed the treatment of metastatic kidney cancer fundamentally. To elaborate the potential impact of TKI therapies, we studied trends in OS for patients with primary metastatic kidney cancer between 1998 and 2014 in Austria. Methods: All patients with primary metastatic kidney cancer aged ≥18 years, diagnosed from 1998-2009 were derived from the ANCR (n=2134). Patients diagnosed from 2004-2006 (n=316) were excluded (transition period of systemic therapies). To evaluate differences in OS between patients treated in preTKI-era and TKI-era, two periods were defined: 1998-2003 (before the introduction of Sunitinib in Austria, P1; n=926) and 2006-2009 (P2; n=542). Follow-up was complete until December 31st, 2014. OS rates were estimated by using the Kaplan-Meier method. The Cox proportional hazard model was used to calculate hazard ratios (HR). Results: A total 1468 patients was included in the analysis. The median age of the study population was 70 yrs (sd ±12) and did not differ between the two eras. The incidence of T1 tumors increased from 6.6% in P1 to 10% in P2 while T4 tumors decreased from 15% to 6.5% (p<0.001). Surgery rate remained stable at 48% (p=0.14). Five-year OS for patients undergoing surgery slightly increased from 16% in P1 to 20% in P2, although not significant (p=0.11). For patients without surgery 5-year OS improved from 4.3% in P1 to 7.9% in P2 (p=0.02). Apart from surgery, survival gain was observed for younger patients (<75 yrs) of 4% (p=0.04) and for T3/T4 tumors of 7% (p=0.008). The risk of death (HR) for patients treated in the TKI-era was reduced compared to the preTKI-era (HR 0.83, 95% CI 0.74-0.93) adjusted for sex, age, T-stage, and surgery. Survival advantage for patients undergoing surgery remained significant (HR: 0.50, 95% CI 0.45-0.57) after adjustment for TKI-era, sex, age, and T-stage. Conclusions: Patients with primary metastatic kidney cancer treated in the TKI era show improved OS compared to the cytokine era. Most benefit was observed in non-surgical patients, younger patients, and for T3/T4 disease. Surgery remains as an important therapy for additional survival benefit.

Immunothérapie en uropathologie

The algorithms for treatment of metastatic cancers are evolving due to positive results obtained with immunotherapy. Therapeutics approaches to stimulate the immune system have already been used in the treatment of kidney and bladder cancer, such as the administration of cytokines and BCG therapy, confirming the immunogenicity of these tumors. The aim of immunotherapies is not only to activate the immune system against tumor cells, but also to take into account the tumor-induced suppressive microenvironment, in particular by removing the anergy of T-cell lymphocytes, and by targeting the co-stimulation inhibitors molecules. Among the genito-urinary cancers, second-line clinical trials have clearly shown that kidney and bladder cancers are sensitive to the inhibition of PD-1/PD-L1 axis and have already achieved FDA approvals for some molecules. Numerous other clinical trials are underway, particularly in first-line treatment in bladder and renal cancers. Refractory testicular cancer could also benefit from these treatments. Other approaches using vaccine therapy especially in castration-resistant prostate cancer are also of interest. We will see, in this chapter dedicated to the urogenital cancers, the benefit of the immunotherapy by resituating it in the genetic and immunological context of each organ. We will also present briefly the therapeutic outlines and the place of biomarkers.

The growth factor of endothelium of vessels and its receptors type I and II in blood serum in patients with kidney cancer: clinical morphological correlations.

The progress in treatment of kidney cancer is related to application of anti-angiogenic medications. Therefore, investigation and searching for new molecular markers characterizing its angiogenic activity is actual still. The purpose of study is to compare VEGF, VEGFR1 and VEGFR2 in blood serum of healthy people, patients with cancer and benign tumors of kidney and to analyze their relationship with main clinical morphological characteristics of neoplasms. The study sampling consisted of 94 patients with cancer and 10 patients with benign tumors of kidney. The control group included 80 individuals. The concentration of analyzed proteins was determined using QuantikineТ (R&D Systems, USA), a reagents' kit for direct immune enzyme analysis. The content of VEGF, VEGFR1 and VEGFR2 in blood serum of patients with cancer of kidney was reliably higher than in control group. The level of VEGF also was increased in patients with benign tumors. Under threshold level of VEGF of 365 pg/ml the diagnostic sensitivity of detection of primary cancer of kidney amounted to 67% and specificity - 70%. The stage of disease and T and N indices were correlated only with VEGFR1 level. The relationship between level of markers and histological structure and degree of differentiation of cancer of kidney was not established. Therefore, VEGF and its receptors have a limited diagnostic value under cancer of kidney but they can be applied for monitoring and prognosis of efficiency of anti-angiogenic therapy.

KIDNEY CANCER INCIDENCE AND MORTALITY IN RUSSIA AND SAINT-PETERSBURG

The paper analyzes data on kidney cancer incidence and mortality in Russia and Saint-Petersburg, highlights the issues related to the diagnosis and treatment of kidney cancer, depending on the stage of the disease and the age of the patient. The incidence of kidney cancer has been steadily increasing over the last ten years, and this is predominantly related to the advances in imaging technology and because of the growth and aging of the population. In Russia, the kidney cancer incidence is expected to increase rapidly due to increases in proportion of early kidney cancer patients that makes it extremely important to improve the organ-preserving treatment of this disease. Morphological verification must necessarily be done both in patients with metastatic cancer and in patients planning to undergo ablation treatment.

Nivolumab as the new standard of metastatic kidney cancer treatment

The last decade was marked by the rapid development of kidney cancer drug treatment and advent of targeted drugs aimed at inhibition of angiogenesis which plays a crucial role in tumor growth. Despite certain success, targeted antiangiogenetic therapy with tyrosine kinase inhibitors, mammalian target of rapamycin inhibitors (mTOR), and monoclonal antibodies against vascular endothelial growth factor (VEGF) in most cases do not achieve long-term remission, are highly toxic, and never lead to full cure for the patients. Development of modern immunological approaches to application of inhibitors of the crucial immune response regulators opens up new possibilities in treatment of disseminated kidney cancer. In this review, results of the studies of nivolumab (PD-1 inhibitor), first checkpoint inhibitor registered for treatment of metastatic kidney cancer are presented.

Surgical treatment for multiple primary bilateral kidney cancer

Surgical treatment for multiple primary bilateral kidney cancer

Possibilities of optimization of the second line targeted therapy for metastatic renal cell carcinoma

Optimization of treatment of metastatic renal cell carcinoma (mRCC) is an important problem of modern oncological urology. Targeted drugs replaced immunotherapy with cytokines and became the new standard of treatment. Their introduction resulted in increased patients» lifespan and fundamentally changed treatment of kidney cancer. Since 2005, 9 targeted drugs and 1 combination of lenvatinib and everolimus were registered and approved for treatment of mRCC. All of these drugs, except cabozantinib, are available in Russia. Currently, in mRCC treatment subsequent prescription of the drugs is used, i. e. patients receive several lines of targeted therapy. We still can»t name the most effective sequence of the 1st and 2nd lines of mRCC therapy due to a lack of clear algorithms of drug prescription. Currently, axitinib, cabozantinib, everolimus, nivolumab, and sorafenib (in alphabetic order) and the combination of lenvatinib and everolimus are recommended for the 2nd line of mRCC therapy. However, there weren’t any direct comparative studies of their effectiveness, and therefore knowledge about differences between the targeted agents can make the selection more straightforward.

Inhibition of the Ras/Raf interaction and repression of renal cancer xenografts in vivo by an enantiomeric iridium(iii) metal-based compound.

Targeting protein-protein interactions (PPIs) offers tantalizing opportunities for therapeutic intervention for the treatment of human diseases. Modulating PPI interfaces with organic small molecules has been found to be exceptionally challenging, and few candidates have been successfully developed into clinical drugs. Meanwhile, the striking array of distinctive properties exhibited by metal compounds renders them attractive scaffolds for the development of bioactive leads. Here, we report the identification of iridium(iii) compounds as inhibitors of the H-Ras/Raf-1 PPI. The lead iridium(iii) compound 1 exhibited potent inhibitory activity against the H-Ras/Raf-1 interaction and its signaling pathway in vitro and in vivo, and also directly engaged both H-Ras and Raf-1-RBD in cell lysates. Moreover, 1 repressed tumor growth in a mouse renal xenograft tumor model. Intriguingly, the Δ-enantiomer of 1 showed superior potency in the biological assays compared to Λ-1 or racemic 1. These compounds could potentially be used as starting scaffolds for the development of more potent Ras/Raf PPI inhibitors for the treatment of kidney cancer or other proliferative diseases.

Surgical treatment of kidney cancer with extended inferior vena cava thrombosis: complications and long-term results

Objective. Analysis of factors affecting results of inferior vena cava (IVC) thrombectomy in patients with renal cell carcinoma. Materials and methods . Nephrectomy with thrombectomy from IVC was performed in 53 patients (31 (58.5 %) males and 22 (41.5 %) females) with extended thrombosis. Patient age was 35–76 years (mean age 58.7 ± 10.1 years). In 36 (68 %) patients stage Т3b was determined (mean thrombus length 5.28 ±0.32 cm), in 17 (32 %) patients – stage Т3с (mean thrombus length – 13.00 ±0.71 cm). Postoperative complications were evaluated in accordance with the Clavien–Dindo classification. Calculations were performed using statistics software SPSS Statistics 16. Results. No intraoperative complications were observed, mean blood loss was 714 (200–4000) ml. Use of the Cell Saver system allowed to perform reinfusion in the majority of patients. Blood transfusion of 200–500 ml was necessary in 15 patients. In 32 (60.3 %) patients no complications were observed. Grade I complications were observed in 2 (3.7 %) patients, grade II – in 15 (28.3 %) patients, IIIА grade – in 2 (3.7 %) patients, and grade IIIВ – in 1 (1.8 %) patient; there wasn’t any grade IV complications. Two (3.8 %) patients died of pulmonary artery thromboembolism. Correlation analysis has shown a high dependency of complications on thrombus size (r = 0.7) and blood loss volume (r = 0.6), and low dependency on tumor size (r = 0.44); complications weren’t affected by patients’ age (r = 0.1) or Karnofsky status (r = 0.0). Median overall survival was 48 months, 3-year survival was 57.1 %, median progression-free survival was 46 months, 3-year progression-free survival was 56.8 %; 90-day morbidity was absent. Three-year overall survival for рN0 was significantly higher than for рN1 (69 % vs. 25 %; р = 0.014). There was no difference in terms of survival between patients with supradiaphragmatic and subdiaphragmatic thrombi (р = 0.14). Conclusion . Results of our study show that surgical treatment of patients with renal cell carcinoma and extended IVC thrombosis is effective.

Acetazolamide Serves as Selective Delivery Vehicle for Dipeptide-Linked Drugs to Renal Cell Carcinoma.

In most cases, cytotoxic drugs do not preferentially accumulate at the tumor site, causing unwanted toxicities and preventing dose escalation to therapeutically active regimens. Here, we show that acetazolamide derivatives, which bind to carbonic anhydrase IX (CAIX) on the surface of kidney cancer cells, selectively deliver payloads at the site of disease, sparing normal organs. Biodistribution studies, performed in tumor-bearing mice with acetazolamide derivatives bearing a technetium-99m chelator complex or a red fluorophore as payload, revealed a preferential tumor accumulation of the compound at doses up to 560 nmol/kg. The percentage of injected dose per gram in the tumor was dose-dependent and revealed optimal tumor:organ ratios at 140 nmol/kg, with a tumor:blood ratio of 80:1 at 6 hours. Acetazolamide, coupled to potent cytotoxic drugs via a dipeptide linker, exhibited a potent antitumor activity in nude mice bearing SKRC-52 renal cell carcinomas, whereas drug derivatives devoid of the acetazolamide moiety did not exhibit any detectable anticancer activity at the same doses. The observation of tumor regression with a noninternalizing ligand and with different cytotoxic moieties (MMAE and PNU-159682) indicates a general mechanism of action, based on the selective accumulation of the product on tumor cells, followed by the extracellular proteolytic release of the cytotoxic payload at the neoplastic site and the subsequent drug internalization into tumor cells. Acetazolamide-based drug conjugates may represent a promising class of targeted agents for the treatment of metastatic kidney cancer, as the majority of human clear cell renal cell carcinomas are strongly positive for CAIX. Mol Cancer Ther; 15(12); 2926-35. ©2016 AACR.

EO9 - When to perform a staging chest-CT scan before surgical treatment for kidney cancer

EO9 - When to perform a staging chest-CT scan before surgical treatment for kidney cancer

Combination immunotherapy in genitourinary malignancies.

Combination immunotherapy has already shown promise in several tumor types, such as melanoma and nonsmall cell lung cancer, and studies are ongoing to evaluate this approach in other malignancies. Trials such as these will only continue to expand as additional immune therapies are shown to have efficacy as single agents in cancer. The purpose of this review is to outline the current landscape of immunotherapy in genitourinary cancer, and to highlight ongoing and pending combination immunotherapy trials in bladder, kidney, and prostate cancers. Immunotherapy agents have long been a part of the treatment armamentarium for patients with bladder, kidney, and prostate cancers, contributing to responses with variable toxicities.In the last year, checkpoint blockade immunotherapy has been Food and Drug Administration approved for renal and bladder cancer, whereas novel vaccines continue to be tested in prostate cancer. The efficacy coupled with mostly mild toxicity of modern immunotherapy make these agents perfect vehicles for combination, sequence, or priming studies to maximize benefit. Published and recently presented combination immunotherapy studies in genitourinary malignancies are summarized. Immune therapy strategies are integral to the treatment of bladder, kidney, and prostate cancers. Though the current experience with combination immunotherapy in these cancers is limited, ongoing and maturing studies of combination immunotherapy discussed herein may lead to improved outcomes for patients and change in standard of care. What is learned from correlative data on tumor microenvironment and systemic immune response before, during and following immunotherapy will be integral to the future design of combination immunotherapy trials.

A Prospective Observational Study for Assessment and Outcome Association of Circulating Endothelial Cells in Clear Cell Renal Cell Carcinoma Patients Who Show Initial Benefit from First-line Treatment. The CIRCLES (CIRCuLating Endothelial cellS) Study (SOGUG-CEC-2011-01)

BackgroundMarkers able to predict the response to antiangiogenics in metastatic clear cell renal cell carcinoma (ccRCC) are not available. The development of new treatment options like immunotherapy are reaching the clinic; therefore, predictors of benefit from these different available treatments are increasingly needed. ObjectiveIn this study, we prospectively assessed the association of circulating endothelial cells (CECs) in peripheral blood with long-term benefit from first-line treatment in ccRCC. Design, setting, and participantsA prospective observational study was designed involving 13 institutions of the Spanish Oncology Genitourinary Group. Adult patients diagnosed with advanced ccRCC who had achieved response or disease stabilization after 3 mo on first-line therapy were eligible. Outcome measurements and statistical analysisCECs were isolated from peripheral blood, captured with ferrofluids coated with monoclonal antibodies directed against the CD146 antigen, and assessed centrally with an automated standardized system. CECs were defined as 4′,6-diamidino-2-phenylindole+, CD105+, and CD45–. Blood samples were systematically taken every 6 wk for 15 mo or until tumor progression, whichever occurred first. Clinical data were externally monitored at all centers. Results and limitationsFrom August 9, 2011, to January 17, 2013, 75 patients were enrolled in the study. Patients with baseline CECs above the median showed a significantly longer progression-free survival than those with low CECs (22.2 mo vs 12.2 mo) with a hazard ratio of 2.5 (95% confidence interval: 1.2–5.3, p=0.016). There was no difference between CEC levels at baseline and at tumor progression (medians of 50 CECs/4ml and 52 CECs/4ml, respectively). ConclusionsUnder antiangiogenic treatment, the detection of higher CEC levels is associated with clinical benefit in terms of progression-free survival in ccRCC. Patient summaryAntiangiogenics are the cornerstone of treatment in kidney cancer. Since they target endothelial rather than tumor cells, we studied the correlation between levels of circulating endothelial cells in peripheral blood and long-term benefit in patients on antiangiogenic therapy. Higher levels were associated with long-term benefit, suggesting that this determination could help to separate best responders from those who could require a more intensive approach.