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Nephrotic syndrome in patients with cancer may be related to the primary malignancy or chemotherapeutic therapy. Solid organ cancers may cause membranous glomerulonephritis manifesting with nephrotic syndrome; other less common histologic presentations include focal and segmental glomerulosclerosis and minimal change disease. In addition, chemotherapy agents can cause renal toxicity by affecting the small blood vessels, glomeruli, tubules, and interstitium. Tyrosine kinase inhibitors such as sunitinib may cause endothelial and podocyte damage leading to renal limited thrombotic microangiopathy, manifested by proteinuria and hypertension. We report a case of an elderly man with gastrointestinal stromal tumor (GIST) on treatment with sunitinib who had as a complication of a thrombotic microangiopathy manifested with nephrotic syndrome and difficult-to-control hypertension, which was controlled by stopping this drug but with a fatal outcome due to its malignant neoplasm.

This study aimed to biochemically and histopathologically investigate the effect of sunitinib on oxidative testicular damage induced by ischemia/reperfusion in rats.Experimental animals were divided into three groups of six rats each: testicular torsion-detorsion (TTD), sunitinib+testicular torsion-detorsion (STD), and sham control (SC). Sunitinib (25mg/kg) was administered orally to the STD group by gavage. Normal saline (0.9% NaCl) was administered orally to the TTD and control groups as the solvent. One hour after administration of sunitinib and 0.9% NaCl, all animal groups were done torsion-detorsion. Then, all the rats were killed by high-dose anesthesia, and their testicles were removed. Biochemical and histopathological examinations were performed on the removed testicular tissues.Malondialdehyde; it was observed that the results in the STD group were close to those of the SC group and statistically significant lower compared to the TTD group (p=0.001). The glutathione values were statistically significantly higher in the STD group compared to the TTD group (p0.001). Nuclear factor kappa B values, revealing a statistically significant difference between the TTD and STD groups (p0.001). The TNF-α levels were measured and indicating that the results of the STD group were statistically significantly lower than those of the TTD group (p0.001). Histopathologically, animal tissues given sunitinib were observed to resemble normal tissues.Sunitinib was shown to prevent histopathological changes in testicular tissue against ischemia/reperfusion damage.

Tyrosine kinase inhibitors (TKI) are anticancer agents widely used for a variety of malignancies including gastrointestinal stromal tumours (GIST). Although generally well-tolerated, TKIs have been associated with a number of adverse events including hypertension, proteinuria and nephrotic syndrome. We present the case of a 70-year-old patient with metastatic GIST on long-standing sunitinib who developed hypertension, oedema and hypoalbuminemia with a rising serum creatinine and was found to have nephrotic syndrome. Workup revealed elevated antiphospholipase A2 receptor (PLA2R) antibody IgG titres and a kidney biopsy confirmed PLA2R-positive membranous nephropathy without findings of thrombotic microangiopathy. Cessation of sunitinib led to reduction in anti-PLA2R antibody IgG titres while resumption, due to concern for cancer progression, led to worsening symptoms. Treatment with rituximab led to undetectable anti-PLA2R IgG titres. We highlight the importance of maintaining a systematic approach for evaluating nephrotic syndrome and provide a case showing that TKIs can exacerbate underlying nephrotic syndrome.

Pembrolizumab plus axitinib improved efficacy over sunitinib in treatment-naive advanced renal cell carcinoma in the KEYNOTE-426 (NCT02853331) study. However, a relatively high incidence of grade 3/4 aminotransferase elevations was observed.To further characterize treatment-emergent aminotransferase elevations in patients treated with pembrolizumab-axitinib.Patients enrolled in KEYNOTE-426 were included in this study.Three Standardized MedDRA Queries for potential hepatic disorders were used to identify patients for the hepatic event analysis subpopulation (HEAS). Alanine aminotransferase events were characterized for time to onset, time to recovery, corticosteroid use, and rechallenge with study treatment(s).The HEAS comprised 189/429 (44%) pembrolizumab-axitinib patients and 128/425 (30%) sunitinib patients. Grade 3/4 hepatic adverse events were more common in the combination arm: 22% (94/429) versus 7% (29/425); 3% (13/429) discontinued the combination due to hepatic adverse events. In the pembrolizumab-axitinib arm, 125/426 patients (29%) had alanine aminotransferase (ALT) ≥3× upper limit of normal (ULN), with median time to onset of 84 d (range, 7-840 d). Among patients with ALT ≥3× ULN, 120/125 (96%) recovered to3× ULN following study treatment interruption/discontinuation, with a median time to recovery of 15 d (3-176 d): 68/120 (57%) received corticosteroids. One hundred patients were rechallenged with one or both study treatment(s): 45/100 (45%) had ALT ≥3× ULN recurrence, and all 45 recovered to ALT3× ULN following study treatment interruption/discontinuation. No fatal hepatic events occurred.A higher incidence of grade 3/4 aminotransferase elevations occurs with pembrolizumab-axitinib. These events should be carefully evaluated and managed with prompt study treatment interruption or discontinuation, with or without corticosteroid treatment. The decision to rechallenge with one or both drugs should be based on severity of event and thorough causality assessment.Renal cell carcinoma patients receiving pembrolizumab-axitinib are at a higher risk of liver enzyme elevations, which could be reversed with appropriate management.

Immune checkpoint inhibitors (ICIs) have reported unprecedented results in the treatment of metastatic renal cell carcinoma (mRCC) patients, as monotherapy or in combination with other anticancer agents. However, little information is available regarding the association between different clinicopathological features and survival in this setting.We performed a meta-analysis aimed at exploring the predictive value of routinely collected clinicopathological data in randomized controlled trials (RCTs) evaluating ICIs plus tyrosine kinase inhibitors (TKIs) in treatment-naïve patients with mRCC.We retrieved all the relevant RCTs through PubMed/Medline, Cochrane Library, and EMBASE; additionally, proceedings of the main international oncological meetings were also searched for relevant abstracts. Eligible studies included RCTs assessing first-line ICI-TKI versus sunitinib in treatment-naïve mRCC patients; the primary endpoint was overall survival (OS), measured as hazard ratio (HR) with corresponding 95% confidence interval (CI).Overall, three phase III RCTs involving 1769 patients with advanced or metastatic RCC were included. Compared with sunitinib, the ICI-TKI combination significantly decreased the risk of death in patients with Eastern Cooperative Oncology Group performance status (ECOG-PS) 0 (HR, 0.66; 95% CI, 0.57-0.76) and ECOG-PS 1 (HR, 0.64; 95% CI, 0.54-0.77). Similarly, the combination was associated with prolonged OS in patients who were65 yr old (HR, 0.57; 95% CI, 0.49-0.67), in mRCC patients ≥65 yr old (HR, 0.75; 95% CI, 0.61-0.90), as well as in male (HR, 0.66; 95% CI, 0.56-0.78) and female (HR, 0.66; 95% CI, 0.52-0.83) patients.According to our results, the magnitude of benefit of the ICI-TKI combination over sunitinib monotherapy in treatment-naïve mRCC patients was consistent across the clinicopathological subgroups. Despite the limitations affecting the analysis, we believe that the results of the current meta-analysis could assist clinicians and researchers in the design and interpretation of future clinical trials on combination therapies in this setting.First-line combinations of an immune checkpoint inhibitor plus a tyrosine kinase inhibitor improved survival in metastatic renal cell carcinoma (mRCC) patients. This survival benefit was consistent across all subgroups of mRCC patients irrespective of clinicopathological features such as patient performance status, age65 and ≥65 yr, and male and female gender.

Objective The role of alternate sequential administration of sunitinib and capecitabine/temozolomide (CAPTEM) in metastatic pancreatic neuroendocrine tumors (PanNETs) remains unexplored. We thus aimed to analyze the efficacy and tolerability of this strategy in advanced grade 1/grade 2 PanNETs. Methods In total, data of 43 patients with metastatic PanNET were collected from a real-world database of a cancer center. Twenty-four patients were treated with sunitinib followed by CAPTEM (group 1), and 19 patients were treated with CAPTEM followed by sunitinib (group 2). Results Twenty-three patients were treated with first-line sunitinib or CAPTEM, and 20 patients were pretreated with somatostatin analog (SSA) or SSA in combination with transcatheter arterial chemoembolization. The objective response rate with first-line treatment was similar in both groups, whereas that with second-line treatment was higher in group 1 than in group 2, albeit with no significant differences (21.1% vs 5.3%, respectively; P = .205). Median progression-free survival (mPFS) for first-line and second-line treatments did not differ between the 2 groups (11 and 12 months vs 12 and 8 months, respectively). Following subgroup analyses, treatment with first-line sunitinib and sunitinib after pretreated SSA had a longer mPFS than that with second-line sunitinib after CAPTEM (11 months vs 8 months, respectively; P = .046), whereas treatment with first-line CAPTEM and CAPTEM after pretreated SSA had an mPFS similar to that of second-line CAPTEM after sunitinib treatment. CAPTEM and sunitinib had similar tolerability. Conclusion Alternating sunitinib and CAPTEM were well tolerated and associated with similar mPFS in grade 1/grade 2 PanNETs. However, larger prospective studies are required to investigate the efficacy of alternate sequential therapies for metastatic PanNET.

Background : Axitinib monotherapy obtained approval in pre-treated metastatic renal cell carcinoma (mRCC) patients and recently in combination with pembrolizumab or avelumab in the first-line setting. However, patient profiles that may obtain increased benefit from this drug and its combinations still need to be identified. Patients and Methods : Retrospective multicentre analysis describing clinical characteristics associated with axitinib long-responder (LR) population by comparing two extreme-response sub-groups (progression-free survival [PFS] ≥9 months versus disease progression/refractory patients [RP]). A multivariate logistic-regression model was used to analyse clinical factors. Efficacy and safety were also analysed. Results : In total, 157 patients who received axitinib in second or subsequent line were evaluated (91 LR and 66 RP). Older age at start of axitinib and haemoglobin levels > LLN were independent predictive factors for LR in multivariate analyses. In LR patients, median (m) PFS was 18.1 months, median overall survival (OS) was 36.0 months and objective response rate (ORR) was 45.5%. In 59 LR patients receiving axitinib in second-line, mPFS was 18.7 months, mOS was 44.8 months and ORR was 43.9%. mOS was significantly longer in second line compared to subsequent lines (44.8 versus 26.5 months; P=0.009). In LR versus RP, mPFS with sunitinib in first-line was correlated with mPFS with axitinib in second-line (27.2 versus 10.9 months P Conclusions : This study confirms the long-term benefits of axitinib in a selected population, helping clinicians to select the best sequential approach and patients who could obtain a greater benefit from axitinib. Microabstract Patients with metastatic renal cell carcinoma (mRCC) who may benefit most from axitinib still need to be identified. AXILONG study confirms long-term benefits in a selected population in which age at axitinib initiation and haemoglobin baseline levels were significantly associated although further validation may be required. First-line sunitinib outcomes were also correlated with prolonged response. These results might be helpful in real-life management of mRCC patients.

Tumoral angiogenesis is a key mechanism involved in the growth and spread of cancer cells. The development of angiogenesis inhibitors, particularly those targeting the Vascular Endothelial Growth Factor (VEGF) pathway, has improved the prognosis and survival of many cancer patients since they were approved in 2005 in France. Vascular Endothelial Growth Factor inhibitors have different mechanisms of action, targeting either the ligand (e.g. bevacizumab, anti-Vascular Endothelial Growth Factor monoclonal antibody; aflibercept, recombinant anti-Vascular Endothelial Growth Factor fusion protein), or its receptors such as tyrosine kinase inhibitors (e.g. sunitinib or sorafenib). These treatments can be combined with conventional chemotherapy, or other anti-cancer therapies, and are associated with variable tolerance depending on the patient's clinical condition and comorbidities. Additionally, angiogenesis inhibition may be associated with cardiovascular and/or kidney toxicity and therefore special monitoring is needed during the treatment duration. Development of hypertension and proteinuria are the commonest renal side effects; these are generally manageable and reversible when treatment is stopped. However, more severe toxicities have been reported such as acute kidney injury, glomerular and/or vascular insults such as thrombotic microangiopathy, and more rarely tubulointerstitial damage. The prescribing physician should be aware of these potentially serious. This article describes the mechanisms of action of antiangiogenic agents and their potential toxicities, with particular respect to the kidneys.

Contains fulltext : 249093.pdf (Publisher’s version ) (Open Access) Cabozantinib is registered in fixed 60 mg dose. However, 46% to 62% of patients in the registration studies needed a dose reduction due to toxicity. Improved clinical efficacy has been observed in renal cell carcinoma patients (RCC) with a cabozantinib exposure greater than 750 μg/L. In our study we explored the cabozantinib exposure in patients with different tumour types. We included RCC patients from routine care and salivary gland carcinoma (SGC) patients from a phase II study with ≥1 measured C(min) at steady-state. The geometric mean (GM) C(min) at the starting dose, at 40 mg and at best tolerated dose (BTD) were compared between both tumour types. Forty-seven patients were included. All SGC patients (n = 22) started with 60 mg, while 52% of RCC patients started with 40 mg. GM C(min) at the start dose was 1456 μg/L (95% CI: 1185-1789) vs 682 μg/L (95% CI: 572-812) (P

INTRODUCTION Neoadjuvant chemotherapy is standard treatment for locally advanced (LABC) or inflammatory breast cancer (IBC). We hypothesized adding sunitinib, a tyrosine kinase inhibitor with anti-tumor and anti-angiogenic activity, to an anthracycline and taxane regimen would improve pathologic complete response (pCR) rates to a prespecified endpoint of 45% in patients with HER2 negative LABC or IBC. PATIENTS AND METHODS We conducted a multicenter, phase II trial of neoadjuvant sunitinib with paclitaxel (S+T) followed by doxorubicin and cyclophosphamide plus G-CSF for patients with HER2 negative LABC or IBC. Patients received sunitinib 25 mg PO daily with paclitaxel 80 mg/m2 IV weekly x12 followed by doxorubicin 24 mg/m2 IV weekly + cyclophosphamide 60 mg/m2 PO daily with G-CSF support. Response was evaluated using pCR in the breast and the Clinical-pathologic scoring + estrogen receptor (ER) and grade (CPS+EG) score. RESULTS Seventy patients enrolled and 66 were evaluable for efficacy. Eighteen patients (27%) had pCR in the breast (10 had ER+ disease and 8 had triple negative disease). When defining response as pCR and/or CPS+EG score ≤ 2, 47% were responders. In ER+ patients, 23 (64%) were responders. The most common toxicities were cytopenias and fatigue. CONCLUSIONS Neoadjuvant S+T followed by AC+G-CSF was safe and tolerable in LABC and IBC. The study did not meet the prespecified endpoint for pCR. However, 47% were responders using pCR and/or CPS+EG score ≤2. ER+ patients had the highest response rate (64%). The addition of sunitinib to neoadjuvant chemotherapy may provide promising incremental benefit for ER+ patients.

WHAT IS KNOWN AND OBJECTIVE Sunitinib is used as a first-line therapy for metastatic renal cell carcinoma. The primary aim of this study was to determine the optimal total sunitinib (sunitinib plus N-desethyl sunitinib) trough concentration for the alternative dosing schedule: 2-week-on and 1-week-off schedule (2/1 schedule). METHODS Patients with metastatic renal cell carcinoma treated with the 2/1 schedule of sunitinib, whose total sunitinib concentrations were available, were recruited for this study. Out of 19 patients, 17 whose sunitinib dosage was not changed until the measurement of drug concentration were eligible for the analysis of the relationship between total sunitinib concentration and clinical outcome. Individual pharmacokinetic parameters in 19 patients were estimated via the Bayesian analysis. RESULTS The onset of severe (grade ≥3) adverse effects among 17 patients during 3 weeks as a first course of sunitinib therapy was observed in 7 (41.2%) patients. The median total sunitinib concentration in patients with severe adverse effects was significantly higher compared with that in patients without severe adverse effects [median: 119 (113-131) vs. 87.8 (77.4-102) ng/mL, p = 0.01]. According to the receiver operating characteristic analysis of the onset of severe adverse effects, the cut-off value of the total sunitinib concentration was 108 ng/mL. Patients with a total sunitinib concentration lower than 108 ng/mL had a longer time to first dose reduction or withdrawal due to adverse effects compared with those with a total sunitinib concentration of 108 ng/mL or higher (p = 0.03). The probability without treatment failure was not significantly different between the two concentration groups. In addition, the estimated sunitinib apparent oral clearance (CL/F) was significantly lower in the severe adverse effects group. Our simulation demonstrated that 0.67-time dose is needed for patients with approximately 90.0 ng/mL of sunitinib concentration on day 7 to maintain the concentration at the same level as the patients with higher CL/F. WHAT IS NEW AND CONCLUSION Maintaining the total sunitinib trough concentrations of less than 108 ng/mL is safe to avoid the onset of serious adverse effects without increasing the treatment failure in patients with metastatic renal cell carcinoma treated with the 2/1 schedule of sunitinib.

Sunitinib is one of the first-line multi-tyrosine kinase inhibitors for metastatic renal cell carcinoma, and resistance to sunitinib continues to be a limiting factor for the successful treatment. As interleukin-6 (IL-6) is overexpressed in sunitinib-resistant cells, the purpose of this study was to explore the potential of IL-6 inhibition with tocilizumab, an IL-6 receptor inhibitor, to overcome resistance. In vitro, two sunitinib-resistant renal cell carcinoma cell lines (Caki-1 and SN12K1) were treated with tocilizumab. A mouse subcutaneous xenograft model was also used. Cell viability was studied by MTT assay, and apoptosis by morphology and ApopTag. Expression of IL-6, vascular endothelial growth factor (VEGF), and Bcl-2 was analyzed by qPCR. In vitro, tocilizumab induced significant cell death, and reduced the expression of IL-6, VEGF, and Bcl-2 in sunitinib-resistant cells. However, the in vitro findings could not be successfully translated in vivo, as tocilizumab did not decrease the growth of the tumors.

Background Vasoactive intestinal peptide-secreting tumor (VIPoma) is a very rare, life-threatening, functioning pancreatic neuroendocrine tumor (pNET). The efficacy of antitumor therapies against functioning symptoms and tumor burden have been poorly described in VIPoma. Objective Describe the impact of treatments on the secretory syndrome, tumor burden and survival in patients with VIPoma. Methods We retrospectively reviewed the records of patients with VIPoma treated in seven French expert centers between 1990 and 2016. Diagnostic of VIPoma was reassessed using strict criteria. We evaluated the antisecretory efficacy (>50 % decrease of daily bowel movements), and antitumor efficacy (RECIST 1.1) of all treatments received. Results Twenty-two patients were included. pNETs were mostly metastatic (77 %) and classified as grade 2 (83 %). Median follow-up was 78.2 months. Surgical excision of nonmetastatic VIPoma effectively controlled the secretory syndrome. Although 4/5 patients had metastatic recurrences, all patients were alive after median post-operative follow-up of 171 months. Among the 87 treatments received for metastatic VIPoma, curative-intent surgery (n = 14), somatostatin analogs alone (n = 11), chemotherapy (n = 23), transarterial liver embolization (TALE) (n = 14), everolimus (n = 10) and sunitinib (n = 7) achieved, respectively, 100 %, 67 %, 83 %, 50 %, 20 % and 100 % antisecretory efficacy. The 5-year OS rate was 63.6 %, with pejorative impact of higher Ki-67 index (P = 0.045) and higher plasma VIP concentration (P = 0.025). Conclusions Surgical resection of localized VIPoma is effective but rarely curative. For metastatic VIPoma, curative-intent surgery, chemotherapy and sunitinib are the therapeutic options that best combined antitumor and antisecretory efficacies.

Vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) frequently induce cardiovascular adverse events, though VEGFR-TKIs contribute to the improvement of the prognosis of patients with malignancies. It is widely accepted that VEGFR-TKIs impair left ventricular systolic functions; however, their effects on diastolic functions remain to be fully elucidated. The purpose of this study was to analyze the impact of VEGFR-TKIs on left ventricular diastolic functions. This study was designed as a retrospective single-center cohort study in Japan. We assessed 24 cases who received VEGFR-TKI monotherapy (sunitinib, sorafenib, pazopanib, axitinib) with left ventricular ejection fraction (LVEF) above 50% during the therapy at the Osaka University Hospital from January 2008 to June 2019. Left ventricular diastolic functions were evaluated by the change in echocardiographic parameters before and after the VEGFR-TKI treatment. Both septal e' and lateral e's decreased after treatment (septal e': before, 6.1 ± 1.8; after, 5.0 ± 1.9; n = 21, P < 0.01; lateral e': before, 8.7 ± 2.8; after, 6.9 ± 2.3; n = 21, P < 0.01). E/A declined after VEGFR-TKIs administration, though not statistically significantly. In 20 cases with at least one risk factor for heart failure with preserved ejection fraction (HFpEF), E/A significantly decreased (0.87 ± 0.34 versus 0.68 ± 0.14; P < 0.05) as well as the septal and lateral e's. These results suggest that treatment with VEGFR-TKIs impairs left ventricular diastolic functions in patients with preserved LVEF, especially in those with risk factors for HFpEF.

Purpose: To evaluate the association between neutrophil-to-lymphocyte ratio (NLR) and efficacy of avelumab plus axitinib or sunitinib. Experimental Design: Adult patients with untreated advanced renal cell carcinoma (RCC) with a clear-cell component, ≥1 measurable lesions, Eastern Cooperative Oncology Group performance status of 0 or 1, fresh or archival tumor specimen, and adequate renal, cardiac, and hepatic function were included. Retrospective analyses of the association between baseline NLR and progression-free survival (PFS) and overall survival (OS) in the avelumab plus axitinib or sunitinib arms were performed using the first interim analysis of the phase 3 JAVELIN Renal 101 trial (NCT02684006). Multivariate Cox regression analyses of PFS and OS were conducted. Translational data were assessed to elucidate the underlying biology associated with differences in NLR. Results: Patients with below-median NLR had longer observed PFS with avelumab plus axitinib [stratified HR, 0.85; 95% confidence interval (CI), 0.634–1.153] or sunitinib (HR, 0.56; 95% CI, 0.415–0.745). In the avelumab plus axitinib or sunitinib arms, respectively, median PFS was 13.8 and 11.2 months in patients with below-median NLR, and 13.3 and 5.6 months in patients with median-or-higher NLR. Below-median NLR was also associated with longer observed OS in the avelumab plus axitinib (HR, 0.51; 95% CI, 0.300–0.871) and sunitinib arms (HR, 0.30; 95% CI, 0.174–0.511). Tumor analyses showed an association between NLR and key biological characteristics, suggesting a role of NLR in underlying mechanisms influencing clinical outcome. Conclusions: Current data support NLR as a prognostic biomarker in patients with advanced RCC receiving avelumab plus axitinib or sunitinib.

Introduction Sunitinib still represents a milestone in the treatment for progressive, well-differentiated, advanced panNETs. Areas covered We performed an evidence reappraisal to critically discuss its safety profile. We included nine studies, five clinical trials and four real-world (RW) studies. Within non-real-world (NRW) studies, diarrhea was the most frequent clinical AE. With regard to G3-4 AEs, fatigue and hypertension were the two most frequent, while neutropenia was the most recurrent hematological one. Considering four real-world trials, hand-foot-syndrome (HFS) was the most frequent clinical any-grade AE of any grade and neutropenia was the most common G3-4. Alongside to the AEs rate, the discontinuation rate of sunitinib due to TRAEs was variable among all the nine selected studies, ranging from 10% to 35% in the NRW setting and from 7% to 31% in the RW setting. Conversely, temporary interruption is an accepted strategy to reduce toxicity, even though not specifically tested in pan-NET. Expert opinion Till now, sunitinib continues to be one of the main therapeutic options for patients with well differentiated advanced panNETs, potentially covering any line of treatment. Therefore, tolerability plays a crucial role to increase adherence to therapy and maximize QoL.

BACKGROUND Both zoledronic acid, a potent bisphosphonate, and the antiangiogenic drug sunitinib are included in anticancer protocols and have also been associated with jaw osteonecrosis. Our aim was to compare the effect of these drugs on tissue repair at tooth extraction sites. METHODS Wistar rats were allocated into four groups: (1) sunitinib; (2) sunitinib/zoledronic acid; (3) zoledronic acid; (4) control group. The animals underwent tooth extractions and maxillae were macro- and microscopically analyzed. RESULTS On macroscopic evaluation, the zoledronic acid group showed a significantly higher frequency of oral mucosal lesion; lesions in the sunitinib/zoledronic acid group were larger, albeit not significantly so. The sunitinib/zoledronic acid group had significantly less epithelium than the zoledronic acid and control group, but showed no significant difference compared to the sunitinib group. The sunitinib/zoledronic acid and zoledronic acid groups did not differ from each other, but had significantly less connective tissue and more non-vital bone and microbial colonies than sunitinib and control groups, whereas these latter two groups did not significantly differ from each other. Vital bone and inflammatory infiltrate did not significantly differ between groups. CONCLUSION Sunitinib alone is not associated with non-vital bone, whereas the sunitinib/zoledronic acid combination and zoledronic acid alone are.

Objectives To evaluate the cost-effectiveness of pazopanib for the treatment of metastatic renal cell carcinoma (mRCC) in the first-line settings from a payer perspective. Methods A state-transition model with three health states was developed to estimate the incremental cost per quality-adjusted life years (QALY) gained for pazopanib compared to sunitinib. A lifelong time horizon was adopted in the base-case analysis. The transition probabilities were estimated based on the COMPRAZ trial, utility weights were taken from literature, and costs were based on estimating medical resource utilization data at King Hussein Cancer Centre (KHCC), deriving unit cost inputs from KHCC databases and the Jordan Food and Drug Administration website. Both costs and outcomes were discounted using 3% rate. The model’s uncertainty was tested using a probabilistic and deterministic sensitivity analyses. Key findings The base-case results showed that pazopanib was dominant when using the listed price for both medications. Pazopanib was associated with an incremental saving of −$10 721.55 and an incremental QALY of 0.08. The results were sensitive to utility values and the progression health state cost. The probabilistic sensitivity analysis showed that the probability of pazopanib being cost-effective compared to sunitinib is around 60–70% at KHCC cost-effectiveness threshold values. However, the result was reversed when the price of sunitinib was reduced by 40% making sunitinib the dominant strategy. Conclusions Pazopanib is a potential cost-effective option in the first-line settings for mRCC when the listed price of sunitinib is used. Therefore, price negotiations are recommended before final listing decisions to get the most cost-saving treatment.

Objective To define the impact of first-line dual therapy involving immune checkpoint inhibitors (ICI) on survival outcomes in patients with advanced renal cell carcinoma (aRCC) of International Metastatic RCC Database Consortium favourable-risk. Materials and Methods Systematic review of Medline, EMBASE, and Cochrane Central Register of Controlled trials were conducted to select all phase II/III randomized clinical trials involving first-line, palliative-intent dual therapy in aRCC patients of favourable-risk. Inverse-variance with random-effects model was used for meta-analysis. Sensitivity analysis with exclusion of immune checkpoint inhibitors (ICI)-ICI combination was conducted. Study outcomes were overall survival (OS) and progression free survival (PFS). Results Seven phase II/III randomized controlled trials (N = 1214) were included in the meta-analysis. There were no significant OS differences detected in the favourable-risk group on dual therapy in comparison to sunitinib monotherapy (HR 0.96, 95%CI 0.73-1.26, P = .79). Sensitivity analysis also did not show significant OS benefit when excluding ICI-ICI regimen (HR 0.99, 95%CI 0.69-1.43, P = .96). PFS was not shown to have significant benefit for dual therapy in the favourable-risk group (HR 0.75, 95%CI 0.50-1.13, P = .17), but it met statistical significance when ICI-ICI regimen was excluded from the analysis (HR 0.63, 95%CI 0.50-0.79, P Conclusion There was no OS benefit when comparing dual therapy vs sunitinib monotherapy in aRCC favourable-risk group. Longer follow-up would be required to definitively detect potential OS benefit, if any. Careful patient-clinician discussion of alternative management options are required prior to initiating dual-therapy in all aRCC favourable-risk group.

Copyright © 2021 The Author(s). Aim: To evaluate the cost-effectiveness of [177Lu]Lu-DOTA-TATE versus relevant comparators for the treatment of neuroendocrine tumours located in the gastrointestinal tract (GI-NETs) and the pancreas (P-NETs). Materials and methods: A three-state partitioned survival model was developed to perform a cost-utility analysis of [177Lu]Lu-DOTA-TATE versus standard of care (high dose Octreotide LAR), everolimus and sunitinib. Effectiveness data for SoC, everolimus and sunitinib were obtained from published Kaplan–Meier survival curves. Given a lack of head-to-head effectiveness data, matching adjusted indirect comparisons (MAICs) were performed to population-adjust [177Lu]Lu-DOTA-TATE survival data based on prognostic factors and derive estimates of relative effectiveness. Health state utilities were estimated from real-world evidence. Drug acquisition costs were taken from nationally published sources (BNF, NICE), and administration costs were based on treatment protocols in [177Lu]Lu-DOTA-TATE studies, combined with nationally published unit costs (PSSRU, DoH reference costs). Incidence of adverse events were estimated using published sources. A discount rate of 3.5% was applied to both utilities and costs, and deterministic and probabilistic sensitivity analyses were performed. Costs were included from an NHS perspective and presented in 2017/18 GBP (and PPP Euros for base case). Results: In GI-NETs, the incremental cost-effectiveness ratio (ICER) of [177Lu]Lu-DOTA-TATE compared to SoC and everolimus was £26,528 (€27,672) and £24,145 (€25,186) per QALY, respectively. In P-NETs, the ICER of [177Lu]Lu-DOTA-TATE compared to SoC was £22,146 (€23,101) or £28,038 (€29,251) dependent on matched population, and £21,827 (€22,766) and £15,768 (€16,445) compared to everolimus and sunitinib, respectively. Conclusions: At a willingness to pay threshold of £30,000, [177Lu]Lu-DOTA-TATE is likely to be a cost-effective treatment option for GI-NET and P-NET patients versus relevant treatment comparators (NHS perspective). Advanced Accelerator Applications (AAA), a Novartis company.

Head-to-head comparisons of the efficacy of treatments for gastroenteropancreatic neuroendocrine tumours (GEP-NETs) have not yet been reported. This study used a series of matching-adjusted indirect comparisons to indirectly compare the effectiveness of [177Lu]Lu-DOTA-TATE to everolimus, sunitinib and best supportive care (BSC) for extending progression-free survival and overall survival in patients with advanced, unresectable gastrointestinal (GI)-NETs and P-NETs. The results of the main analysis suggest that after accounting for differences in key prognostic variables, the hazard of progression was 62% (hazard ratio [HR], 0.38; confidence interval [CI]95 0.25–0.58) and 65% (HR 0.35 CI95 0.21–0.59) lower in patients with GI-NETs treated with [177Lu]Lu-DOTA-TATE than in those treated with everolimus and BSC, respectively. Similarly, the hazard of progression was 64% (HR 0.36 CI95 0.18–0.70), 54% (HR 0.46 CI95 0.30–0.71) and 79–87% (HR 0.21 CI95 0.13–0.32; HR 0.13 CI95 0.08–0.22) lower in patients with P-NET treated with [177Lu]Lu-DOTA-TATE than in those treated with sunitinib, everolimus and BSC, respectively. The hazard of death was 58% (HR 0.42 CI95 0.25–0.72), 47% (HR 0.53 CI95 0.33–0.87) and 44–64% (HR 0.56 CI95 0.36–0.90; HR 0.34 CI95 0.20–0.57) lower in P-patients with NET treated with [177Lu]Lu-DOTA-TATE than in those treated with sunitinib, everolimus and BSC, respectively. While our results must be interpreted with caution given the non-randomised nature of the comparisons and the potential for residual confounding, the magnitude of the effect sizes we observe and their consistency across comparators suggest that [177Lu]Lu-DOTA-TATE may be a more effective treatment option than everolimus, sunitinib and BSC in advanced, unresectable GEP-NETs.

BackgroundThe most well-known cause of cancer deaths identified in female is breast cancer. Several drugs approved by the food and drug administration (FDA) for the treatment of breast cancer may have adverse health effects. This research is aimed at developing a QSAR model and utilize it to predict the inhibitive activities of newly designed novel compounds, examine their ADMET and drug-likeness properties and carry out molecular docking studies between the designed compounds and the VEGFR-2 receptors in order to identify the essential amino acid residues involved in protein–ligand interactions and possible mechanism of action of the designed compounds.ResultsThe first model was selected as the best because of its fitness statistically with the following assessment parameters:R2train = 0.832,R2adj = 0.79,R2ext = 0.62,Q2 = 0.68, and LOF = 0.14509. Compound 11 was selected as a template to design new powerful compounds based on its low residual and high pIC50values. Majority of the designed compounds has predicted pIC50greater than that of the lead compound and the standard drug (Sunitinib) used as reference. Molecular docking studies results of the designed compounds revealed that they have higher docking scores than the template and the reference drug (Sunitinib) and are found to bind to the VEGFR-2 receptor in a similar manner to the reference drug. Pharmacokinetics and ADMET properties revealed that the designed compounds passed drug-likeness criteria because they did not violate more than 1 Lipinski’s rule of Five, They are uniformly distributed to the brain and are assumed to penetrate the central nervous system and finally they are all found to non-toxic and orally bioavailable.ConclusionThe developed model was therefore found to be efficient in predicting the pIC50of Anti breast cancer compounds that are yet to be synthesized and it also help in reducing the cost and synthetic duration the compounds. The result of this research confirmed that the designed compounds may be developed as novel VEGFR-2 inhibitors.

This case presents a 68-yr-old female patient with primary metastatic nonclear renal cell carcinoma (RCC) with multiple bone lesions. The patient underwent a single resection of skull bone lesion (diagnostic for poorly differentiated carcinoma of unknown origin) and cytoreductive nephrectomy. The pathology of the kidney specimen demonstrated an oncocytic papillary RCC. Within 3 mo, she developed skeletal progressive disease and was started on systemic therapy (sunitinib). After initial stabilization, bone metastasis progressed during the third cycle of sunitinib and required second-line therapy (cabozantinib). One of the major unmet needs in non-clear cell RCC is the lack of specific systemic therapy. Data on immunotherapy are still limited. Inclusion of these patients in clinical trials is strongly recommended. PATIENT SUMMARY: Patients with metastatic kidney cancer who present with the less common histological subtype (non-clear cell) have poor survival. In this case, the patient responded to second-line therapy. Very few therapies provide response to treatment. Patients should be offered participation in clinical trials testing combinations with immunotherapy.

Background The CARMENA trial in patients with metastatic renal cell carcinoma (mRCC) demonstrated that treatment with sunitinib alone was noninferior to cytoreductive nephrectomy (CN) followed by sunitinib (nephrectomy⬜sunitinib). Objective The objective of this study was to provide updated overall survival (OS) outcomes of CARMENA and assess whether some subgroups may still benefit from upfront CN. Design, setting, and participants CARMENA was a phase III trial in 450 patients with mRCC enrolled from 2009 to 2017. Intervention Patients in the intention-to-treat population received nephrectomy⬜sunitinib (standard of care [SOC]; n = 226) or sunitinib alone (n = 224). Outcome measurements and statistical analysis Primary endpoint was OS, assessed using an updated data cut-off (October 2018; median OS event-free follow-up, 36.6 mo). Patients were reclassified by risk using International Metastatic RCC Database Consortium (IMDC) criteria. Results and limitations Sunitinib alone was noninferior to nephrectomy⬜sunitinib (hazard ratio [HR], 0.97; 95% confidence interval, 0.79⬜1.19; p = 0.8) and demonstrated longer median OS (19.8 mo vs 15.6 mo, respectively). For patients with two or more IMDC risk factors, OS was significantly longer with sunitinib alone than with nephrectomy⬜sunitinib (31.2 mo vs 17.6 mo, respectively; HR, 0.65; p = 0.03). For patients with one IMDC risk factor, OS was longer for nephrectomy⬜sunitinib versus sunitinib alone although not significantly (31.4 mo vs 25.2 mo; HR, 1.30; p = 0.2). The post hoc nature of the subgroup analyses may limit their interpretation. Conclusions Sunitinib alone was noninferior compared with nephrectomy⬜sunitinib, suggesting that CN should not be considered SOC in patients with mRCC requiring systemic treatment. Certain subgroups, including patients with one IMDC risk factor, may still benefit from upfront CN. Patient summary We assessed the survival of patients with metastatic kidney cancer in a clinical trial. Patients treated with sunitinib on its own had the same survival as patients who had surgery before sunitinib treatment. We conclude that surgery may not be necessary for some patients with metastatic kidney cancer.

OBJECTIVES To study the effects of adjuvant therapy in patients with sarcomatoid renal cell carcinoma (sRCC) enrolled in the randomised phase III clinical trial E2805. PATIENTS AND METHODS The original trial (E2805) was a randomised, double-blinded phase III clinical trial comparing outcomes in 1943 patients with RCC accrued between 2006 and 2010 and treated with up to 1 year of adjuvant placebo, sunitinib, or sorafenib. The present study analyses the cohort of patients with sRCC that participated in E2805. RESULTS A total of 171 patients (8.8%) had sarcomatoid features. Of these, 52 patients received sunitinib, 58 received sorafenib, and 61 received placebo. Most patients were pT3-4 (71.1%, 63.7%, and 70.5%, respectively); 17.3%, 19.0%, and 27.9% had pathologically positive lymph nodes; and 59.6%, 62.1%, and 62.3% of the patients were University of California Los Angeles (UCLA) Integrated Staging System (UISS) very-high risk. In 49% of patients with subsequent development of metastatic disease, recurrence occurred in the lung, followed by 30% in the lymph nodes, and 13% in the liver. There was a high local recurrence rate in the renal bed (16%, 29%, and 18%, respectively). The 5-year disease-free survival (DFS) rates were 33.6%, 36.0%, and 27.8%, for sunitinib, sorafenib and placebo, respectively (hazard ratio [HR] 0.74, 95% confidence interval [CI] 0.45-1.20 for sunitinib vs placebo, and HR 0.82, 95% CI 0.53-1.28 for sorafenib vs placebo). CONCLUSIONS Adjuvant therapy with sunitinib or sorafenib did not show an improvement in DFS or OS in patients with sRCC.

Background Thymic carcinomas are rare aggressive mediastinal tumors with a median survival of 2 years. Observation We present a pediatric patient who was diagnosed with metastatic thymic carcinoma and showed continuous improvement of his primary mass and lung metastases with a regimen of cisplatin/docetaxel followed by long-term maintenance therapy with sunitinib for over 5 years. Conclusions This report demonstrates a long-term positive treatment effect using chemotherapy followed by sunitinib in an advanced thymic carcinoma. We are not aware of other reports of pediatric patients with metastatic thymic carcinoma treated with sunitinib maintenance who maintained a durable response for this prolonged period of time.

Although combination immune checkpoint inhibitor (immuno‐oncology [IO]) therapy is the first‐line treatment for metastatic renal cell carcinoma (mRCC), it mostly causes resistance and tumor regrowth. Therefore, an optimal second‐line therapy is necessary. Such therapy typically comprises vascular endothelial growth factor receptor‐tyrosine kinase inhibitors (VEGFR‐TKIs). This study was aimed at comparing the efficacy of two TKIs—axitinib and sunitinib—in mRCC patients. From January 2008 to October 2018, we registered 703 mRCC patients from 8 Japanese institutes. Of these, 408 patients received axitinib or sunitinib as the first‐line treatment. Thereafter, efficacy and survival rate were compared between the axitinib and sunitinib groups. To reduce the effects of selection bias and potential confounders, propensity score matching analysis was performed. Axitinib and sunitinib were administered in 274 and 134 patients, respectively. More than 25% of the patients received nivolumab sequence therapy. To calculate the propensity scores for each patient, we performed multivariate logistic regression analysis. The objective response rate, progression‐free survival (PFS), cause‐specific survival, and overall survival (OS) were significantly better in the axitinib group than in the sunitinib group. Furthermore, the OS was better in the nivolumab‐treated patients in the axitinib group. Axitinib showed higher efficacy and afforded greater survival benefits than did sunitinib when administered as first‐line therapy in mRCC patients. Thus, from among VEGFR‐TKIs, axitinib might be a possible option for application in the middle of IO drug‐based treatment sequences., Compared to sunitinib, axitinib showed higher efficacy and afforded greater survival benefits as first‐line therapy in patients with metastatic renal cell carcinoma. Axitinib might be better than sunitinib for application in the middle of IO drug‐based treatment sequences.

Background Clinical effectiveness and safety data of pazopanib in patients with advanced or mRCC in real-world setting from Asia Pacific, North Africa, and Middle East countries are lacking. Methods PARACHUTE is a phase IV, prospective, non-interventional, observational study. Primary endpoint was the proportion of patients remaining progression free at 12 months. Secondary endpoints were ORR, PFS, safety and tolerability, and relative dose intensity (RDI). Results Overall, 190 patients with a median age of 61 years (range: 22.0-96.0) were included. Most patients were Asian (70%), clear-cell type RCC was the most common (81%), with a favourable (9%), intermediate (47%), poor (10%), and unknown (34%) MSKCC risk score. At the end of the observational period, 78 patients completed the observational period and 112 discontinued the study; 60% of patients had the starting dose at 800 mg. Median RDI was 82%, with 52% of patients receiving < 85%. Of the 145 evaluable patients, 56 (39%) remained progression free at 12 months, and the median PFS was 10 months (95% CI: 8.48-11.83). 19% of patients (21/109) were long-term responders (on pazopanib for >= 18 months). The best response per RECIST 1.1 was CR/PR in 24%, stable disease in 44%, and PD in 31%. Most frequent (> 10%) TEAEs related to pazopanib included diarrhoea (30%), palmar-plantar erythrodysesthesia syndrome (15%), and hypertension (14%). Conclusions Results of the PARACHUTE study support the use of pazopanib in patients with advanced or mRCC who are naive to VEGF-TKI therapy. The safety profile is consistent with that previously reported by pivotal and real-world evidence studies., Novartis Pharmaceuticals Corporation, The PARACHUTE study was sponsored by Novartis Pharmaceuticals Corporation; pazopanib is an asset of Novartis AG as of 1 March 2015.

Aim: Hollow-fiber-based supported liquid membrane was modified utilizing nanostructures such as graphite, graphene oxide or nitrogen-doped graphene oxide, for electro-membrane extraction (EME) of imatinib and sunitinib from biological fluids. By applying these conductive nanostructures, a low-voltage EME device (6.0 V) was fabricated. Materials & methods: A response surface methodology through central composite design was used to evaluate and optimize effects of various essential factors that influence on normalized recovery. Results: Optimal extraction conditions were set as, 1-octanol with 0.01 % (w/v) graphene oxide functioning as the supported liquid membrane, an extraction time of 17.0 min, pH of the acceptor and the donor phase of 2.8 and 7.9, respectively. Conclusion: The method was successfully applied to quantify imatinib and sunitinib in biological fluids.

Background The efficacy of tyrosine kinase inhibitor (TKI)-based therapy after previous immuno-oncology therapy (IO) failure has been addressed before. However, summary efficacy estimates have never been generated in these reports. We addressed this void. Material and methods We systematically examined TKI efficacy after IO-failure and generated weighted median progression-free survival (PFS) estimates for Pazopanib, Axitinib, Cabozantinib, Sunitinib. A systematic review according to PRISMA was conducted. PubMed and abstracts were queried. Only studies proving median PFS were included. Weighted medians were computed for each TKI alternative. Results Of 245 articles, nine eligible studies were included in the current study with 952 analysed patients. Weighted PFS medians after any previous IO-based therapy were respectively 13.7 (range from 4.6 to 24.4), 8.1 (range from 4.7 to 13.2), 8.5 (range from 4.7 to 15.2) and 6.9 months (range from 2.9 to 11.6) for Pazopanib, Axitinib, Cabozantinib, Sunitinib. Specific second-line weighted PFS median was 14.8 months (range from 5.6 to 24.4), 10.1 months (range from 6.4 to 13.2), 8.7 months (range from 4.7 to 15.2) and 6.0 months (range from 2.9 to 8.0) for Pazopanib, Axitinib, Cabozantinib, Sunitinib, respectively, after first-line IO. Conclusion Pazopanib results in the longest weighted median PFS, after previous IO-failure, regardless of treatment line, as well as in specific second-line, post-first-line IO failure settings. Pending novel studies, Pazopanib appears to represent the most promising treatment option after prior IO.

BACKGROUND: Substantial racial and socioeconomic disparities in metastatic RCC (mRCC) have persisted following the introduction of targeted oral anticancer agents (OAAs). The relationship between patient characteristics and OAA access and costs that may underlie persistent disparities in mRCC outcomes have not been examined in a nationally representative patient population. METHODS: Retrospective SEER-Medicare analysis of patients diagnosed with mRCC between 2007–2015 over age 65 with Medicare part D prescription drug coverage. Associations between patient characteristics, OAA receipt, and associated costs were analyzed in the 12 months following mRCC diagnosis and adjusted to 2015 dollars. RESULTS: 2,792 patients met inclusion criteria, of which 32.4%received an OAA. Most patients received sunitinib (57%) or pazopanib (28%) as their first oral therapy. Receipt of OAA did not differ by race/ethnicity or socioeconomic indicators. Patients of advanced age (> 80 years), unmarried patients, and patients residing in the Southern US were less likely to receive OAAs. The mean inflation-adjusted 30-day cost to Medicare of a patient’s first OAA prescription nearly doubled from $3864 in 2007 to $7482 in 2015, while patient out-of-pocket cost decreased from $2409 to $1477. CONCLUSION: Race, ethnicity, and socioeconomic status were not associated with decreased OAA receipt in patients with mRCC; however, residing in the Southern United States was, as was marital status. Surprisingly, the cost to Medicare of an initial OAA prescription nearly doubled from 2007 to 2015, while patient out-of-pocket costs decreased substantially. Shifts in OAA costs may have significant economic implications in the era of personalized medicine.

Background As use of oral cancer therapies increases, patient adherence has become critical when evaluating the effectiveness of therapy. In a phase III trial for renal cell carcinoma, we: (a) characterized adherence to sorafenib, sunitinib, and/or placebo and (b) identified factors associated with non‐adherence. Methods ECOG‐ACRIN E2805 was a double‐blind, placebo‐controlled, randomized trial comparing adjuvant sorafenib or sunitinib in patients with resected primary renal cell carcinoma at high risk for recurrence. We used patient‐completed pill diaries to measure adherence as the number of pills taken divided by the number of pills prescribed. Log‐binomial regression was used to identify correlates of non‐adherence (, In a randomized clinical trial for renal cell carcinoma, adherence to oral therapy was lower (85%) than adherence to placebo (95%). Adherence was also worse among racial/ethnic minorities, patients experiencing certain toxicities, and high volume enrolling sites, highlighting several challenges to address in clinical practice as oral therapies become increasingly common.

Background Renal cell carcinoma (RCC) contributed to 403,262 new cases worldwide in 2018, which constitutes 2.2% of global cancer, nevertheless, sunitinib, one of the major targeted therapeutic agent for RCC, often developed invalid due to resistance. Emerging evidences suggested sunitinib can impact tumor environment which has been proven to be a vital factor for tumor progression. Methods In the present study, we used ssGSEA to extract the immune infiltrating abundance of clear cell RCC (ccRCC) and normal control samples from GSE65615, TCGA, and GTEx; key immune cells were determined by Student's t‐test and univariable Cox analysis. Co‐expression network combined with differentially expressed analysis was then applied to derive key immune‐related genes for ccRCC, followed by the identification of hub genes using differential expression analysis. Subsequently, explorations and validations of the biological function and the immune‐related and sunitinib‐related characteristics were conducted in KEGG, TISIDB, Oncomine, ICGC, and GEO databases. Results We refined immature dendritic cells and central memory CD4 T cells which showed associations with sunitinib and ccRCC. Following, five hub genes (CRYBB1, RIMBP3C, CEACAM4, HAMP, and LYL1) were identified for their strong relationships with sunitinib and immune infiltration in ccRCC. Further validations in external data refined CRYBB1, CEACAM4, and HAMP which play a vital role in sunitinib resistance, immune infiltrations in ccRCC, and the development and progression of ccRCC. In conclusion, our findings could shed light on the resistance of sunitinib in ccRCC and provide novel biomarkers or drug targets for ccRCC., We identified five hub genes (CRYBB1, RIMBP3C, CEACAM4, HAMP, and LYL1) related to immune infiltration, sunitinib in renal carcinoma. External validation refined CRYBB1, CEACAM4 and HAMP which played a vital role in the development and progression of ccRCC and implicated in sunitinib resistance and immune infiltrations in ccRCC.

Patients with metastatic renal cell carcinoma (mRCC) are often elderly and have various comorbidities, including cardiovascular diseases. Although these patients have extensive co-exposure to targeted therapy and cardiovascular drugs, the impact of this co-exposure on outcomes for patients with mRCC remains unclear. Our objective was to evaluate the association between the use of cardiovascular medication and survival of patients with mRCC. The study included 343 consecutive patients with mRCC treated with sunitinib or pazopanib in the first line. Clinical data obtained from the Renal Cell Carcinoma Information System (RENIS) clinical registry and hospital information systems were retrospectively analyzed. Progression-free survival (PFS) and overall survival (OS) were compared according to the use of common medications, including antihypertensives (i.e., β-blockers [BBs], angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, calcium channel blockers, and diuretics), acetylsalicylic acid (aspirin), statins, and proton pump inhibitors. The univariate Cox analysis evaluating the impact of the assessed comedications on patient survival revealed that only BBs were significantly associated with PFS (hazard ratio [HR] 0.533, p

Background We performed subgroup analyses of the AFTER I-O study to clarify the association of time-to-treatment failure (TTF) and discontinuation reason of prior immune-oncology (I-O) therapy, and molecular targeted therapy (TT) regimen with the outcomes of TT after I-O. Methods The data of Japanese metastatic renal cell carcinoma patients treated with TT after nivolumab (NIVO) (CheckMate 025) or NIVO + ipilimumab (IPI) (CheckMate 214) were retrospectively analyzed. The objective response rates (ORRs), progression-free survival (PFS) and overall survival (OS) of TT after I-O were analyzed by subgroups: TTF (, Efficacy of molecular targeted therapy after immune-oncology therapy was favorable without new safety signals, regardless of time to treatment failure and reason for discontinuation of prior I-O, and TT regimen.

Xudong Zhu,1,2,&ast; Xingming Zhang,1,2,&ast; Guangxi Sun,1,2,&ast; Zhenhua Liu,1,2,&ast; Haoran Zhang,1,2 Yaojing Yang,1,2 Yuchao Ni,1,2 Jindong Dai,1,2 Sha Zhu,1,2 Junru Chen,1,2 Jinge Zhao,1,2 Zhipeng Wang,1,2 Hao Zeng,1,2 Pengfei Shen1,2 1Department of Urology, West China Hospital, Sichuan University, Chengdu, 610041, People’s Republic of China; 2Institute of Urology, West China Hospital, Sichuan University, Chengdu, 610041, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Pengfei ShenDepartment of Urology, West China Hospital, Sichuan University, No. 37 Guoxue Xiang, Chengdu, 610041, Sichuan, People’s Republic of ChinaEmail cdhx510@163.comHao ZengDepartment of Urology, West China Hospital, Sichuan University, No. 37 Guoxue Xiang, Chengdu, 610041, Sichuan, People’s Republic of ChinaEmail kucaizeng@163.comPurpose: To investigate the survival benefit and safety of individualized schedules for sunitinib in patients with metastatic renal cell carcinoma (mRCC) through plasma concentration monitoring.Methods: A total of 105 patients with mRCC were enrolled. The schedule was adjusted in two ways: therapeutic drug monitoring (TDM) and toxicity-adjusted schedule (TAS). One group of patients were without any schedule adjustment (maintained schedule, MAS). Progression-free survival (PFS), overall survival (OS), tumor response, and adverse events (AEs) were compared. The relationship between AEs and steady-state concentration or consecutive monitoring curves was explored. Further monitoring of individualized schedules was also conducted.Results: Based on the plasma concentration, the schedules of 18 patients were adjusted in the TDM group. The schedules were adjusted in 37 patients due to severe AEs in the TAS group, while 50 patients were without any schedule adjustment. The median PFS and OS were better in the TDM group than the other two groups (p = 0.001 and p = 0.004, respectively). Univariate and multivariate analyses indicated that TDM could decrease the risk of death independently (p = 0.026). Moreover, the incidence of grades 3/4 AEs decreased from 88.9% to 33.3% in the TDM group (p = 0.001). Sunitinib concentration in 150– 200ng/mL was regarded as a “transitional zone” due to severe AEs mainly happened when concentration elevated over it. After TDM, further plasma concentration monitoring indicated that individualized schedules enabled sunitinib concentration to fluctuate in a much safer range.Conclusion: Treatment-related toxicities could be minimized through plasma concentration monitoring. Patients with adjusted schedules by therapeutic drug monitoring could achieve better survival benefits.Keywords: sunitinib, plasma concentration, metastatic renal cell carcinoma, individualized schedule adjustment, clinical outcomes

Renal cancer is a common malignancy. The frequency of renal cell carcinoma (RCC) in the structure of oncological diseases is steadily increasing. Despite the migration of the stage towards an increase in the frequency of primary detection of localized forms of the disease, renal cancer belongs to the aggressive and unpredictable malignant neoplasms. One third of patients already have distant metastases at the time of diagnosis. Surgery is the only radical method of treatment of renal cancer. However, despite the successes of surgery in the treatment of RCC, according to various data, more than 30% of radically operated patients show dissemination of the tumor process during follow-up. Radiation therapy and chemotherapy are ineffective in treating metastatic RCC (mRCC). The results of nonspecific immunotherapy in the treatment of metastatic renal cancer were also unsatisfactory. Progress in the study of molecular biology has led to the discovery of a new group of anti-tumor drugs related to angiogenesis inhibitors. The use of targeted therapies has increased the efficacy of drug therapy in the treatment of mRCC several times over the use of cytokine immunotherapy. One of the first such drugs registered in 2007 for the treatment of mRCC was sunitinib, which in a number of clinical trials has demonstrated the greatest efficacy and acceptable toxicity. Along with new drug regimens, the multikinase inhibitor sunitinib remains the drug of choice for first-line therapy of inoperable locally advanced and disseminated clear cell and non-small cell RCC in patients with favorable prognosis. The literature review presents a critical analysis of the data related to sunitinib research in kidney cancer and changes in the position of monotherapy with this drug in advanced forms of the disease.

Introduction. Renal cell carcinoma is responsible for 3% of all cancers, with the highest incidence occurring in Western countries. Additionally, in patients with osseous metastasis, only 3% occur within the tibia. Rarely, a patient presents with a primary complaint of lower limb pain in advanced metastatic renal cell carcinoma. Case Presentation. The patient arrived at the emergency department with a primary complaint of left ankle pain. Ankle X-rays demonstrated a lytic lesion involving the medial malleolus with possible metastatic disease. CT scan confirmed a tumor within the right kidney. The patient was treated with a laparoscopic radical nephrectomy with histopathologic confirmation of clear cell renal cell carcinoma. Biopsy was then performed of the tibial lesion, confirming metastatic clear cell renal cell carcinoma. The tibial lesion was treated with local radiotherapy, and because of the progression of the tibia lesion, a decision was made to amputate the leg. Additionally, the patient was enrolled to sunitinib treatment and was disease free at one year of follow-up. 13 months after diagnosis of cancer, she was suffering a major stroke of the brain that caused her to die. Conclusion. The treatment of patients with osseous metastases of renal cell cancer depends on the number of metastases, location of metastases, and overall health of the patient. We performed an overview of available literature and provided a summary regarding the use of cytoreductive nephrectomy, local therapy, target therapy, and bone-targeting agents in the treatment of metastatic renal cell cancer.

Background. Kidney renal clear cell carcinoma (KIRC) is the most prevalent renal malignancy. The therapeutic strategies for advanced KIRC are very few, with only sunitinib being widely approved. Mutations in the PIK3CA gene can affect tumor cell proliferation, metastasis, and patients’ survival. Methods. Bioinformatics analysis was performed to explore the expression and clinical significance of PIK3CA in KIRC. Moreover, qRT-PCR was conducted to verify the result. Results. Subgroup analyses of KIRC tissue based on gender, tumor grade, and cancer stage indicated downregulation of PIK3CA mRNA expression. The KIRC patients with high PIK3CA expression indicated a better overall survival, progression-free survival, and disease-free survival. A predictive nomogram was constructed and demonstrated that the calibration plots for the 3-year and 5-year OS rates were predicted relatively well compared with an ideal model in the TCGA KIRC cohort. The validation study revealed that downregulation of PIK3CA in KIRC tissues and low PIK3CA expression had a poor overall survival with an AUC of 0.775 in the ROC curve. Moreover, Cox regression analysis revealed that PIK3CA expression and clinical stage were independent factors affecting the prognosis of KIRC patients. PIK3CA expression was found to be significantly associated with the abundance of immune cells and immune biomarker sets. PIK3CA and associated genes were found to be mainly associated with immune response and the JAK-STAT signaling pathway. Conclusion. We identified PIK3CA as a potential biomarker for prognosis correlated with immune infiltrates in KIRC. Further studies should focus on the functions of PIK3CA in KIRC carcinogenesis.

Background: Hemochrome parameters at the diagnosis of metastatic renal cell carcinoma (mRCC) and the development of macrocytosis during sunitinib therapy are considered prognostic. Objective: To evaluate the prognostic role of hematologic parameters and macrocytosis in mRCC treated with sunitinib. Methods: We analyzed clinical data of 100 patients with mRCC treated with sunitinib as first-line therapy in a retrospective multicenter study. We calculated neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR) at baseline and erythrocyte mean corpuscular volume (MCV) during therapy. We considered the following cutoffs: NLR >3, PLR >150, LMR 100 fl. Clinical data histology, prior nephrectomy, Fuhrman grading, metastatic sites, Memorial Sloan-Kettering Cancer Center score, and Heng score were collected. Overall survival (OS) and progression-free survival (PFS) were calculated. Univariate and multivariate analysis using Cox regression model with time-dependent (macrocytosis) covariate were applied. Results: At the univariate analysis, low LMR was associated with shorter PFS and OS ( p = 0.02 and p = 0.06, respectively). High PLR was associated with worse PFS ( p = 0.005); median OS was 23 vs 28 months ( p = 0.13). At the multivariate analysis, poor risk (Heng score), low LMR, and high PLR were associated with shorter PFS (hazard ratio 7.1, 1.5, and 2, respectively); poor PS and poor risk (Heng score) were related to worst OS. Macrocytosis was observed in 26 patients and was not prognostic of survival. Conclusions: In our cohort of patients with mRCC treated with sunitinib, low LMR (>3) and high PLR (>150) were associated with shorter PFS. Macrocytosis was not prognostic.

Pyoderma gangrenosum is a rare ulcerative dermatosis. It may be caused by some drugs, including small molecule tyrosine kinase inhibitors (TKIs). The aim of this study was to evaluate the reported evidence of pyoderma gangrenosum associated with the use of these drugs. A systematic electronic literature search of PubMed and Embase was conducted. In these databases, search terms describing pyoderma gangrenosum were combined with TKIs. Fifteen case reports (eight cases associated with sunitinib, two with imatinib, two with ibrutinib, one with gefitinib, one with pazopanib, and one with dabrafenib and trametinib) were identified over the 14 years. The average Naranjo score of these cases is 6.6, which indicates a probable adverse drug reaction. Pyoderma gangrenosum is a probable and reversible drug reaction associated with some TKIs. Detailed medical history can help to prompt diagnosis of drug-induced pyoderma gangrenosum. Clinicians should be aware of TKI-associated pyoderma gangrenosum when caring for the skin of oncologic patients undergoing therapy with kinase inhibitors.

Background To explore the possible mechanism by which curcumin reverses the sunitinib resistance in clear cell renal cell carcinoma (ccRCC). Methods A sunitinib-resistant ccRCC cell model was established. The MTT assay was used to determine the half maximal inhibitory concentration (IC50) and drug resistance (DR) index. The effects of curcumin plus sunitinib or sunitinib alone on drug-resistant cell lines were verified by the cell counting kit-8 (CCK-8)assay, colony formation assay, and apoptosis assay. The concentration of iron ions in the cell lines was analyzed using an Abcam Iron Assay Kit. The expressions of ADAMTS18 gene and ferroptosis-related proteins (NCOA4, FTH1 and p53) after curcumin plus sunitinib treatment were analyzed by reverse transcription polymerase chain reaction (RT-PCR) and Western blotting. After transfection of curcumin plus sunitinib/sunitinib alone-treated drug-resistant cell lines with si-ADAMTS18, cell proliferation activity was assessed by the CCK-8 assay, and the protein expression levels of ADAMTS18, NCOA1, FTH1 and p53 were analyzed by Western blotting. After treatment with ferroptosis-1 (Fer-1; a ferroptosis inhibitor), the cell proliferation activity of drug-resistant cell lines treated with curcumin plus sunitinib/sunitinib alone was reassessed using the CCK-8 assay. Results Curcumin plus sunitinib inhibited the proliferation of sunitinib-resistant ccRCC cells (P0.05). Ferroptosis inhibitors reversed the inhibitory effect of curcumin on sunitinib-resistant ccRCC cell lines. Conclusions Curcumin can reverse the sunitinib resistance in ccRCC, possibly by upregulating the expression of the ADAMTS18 gene to induce ferroptosis.

While immunotherapy with nivolumab is promising for patients with renal cell carcinoma (RCC), overactivation of the immune system can lead to serious side effects. Immune-related meningoencephalitis without a viral or microbial etiology is a rare complication that may occur in patients treated with checkpoint inhibitors (CPI). Herein, we report a 66-year-old man who underwent a partial nephrectomy which revealed a papillary RCC with clear cell component. Three years later, an abdomen and pelvic CT revealed metastatic lesions in the left psoas muscle and in the left 12th rib. The patient was treated with pazopanib which was discontinued after 2 weeks due to significant hepatic and renal toxicity. He subsequently started sunitinib. Two months later, a chest, abdomen, and pelvic CT demonstrated progressive metastatic RCC in the retroperitoneal mass of the left psoas muscle and paraspinal musculature as well as a left renal mass. The patient was treated with 7 cycles of the CPI nivolumab. He was subsequently hospitalized for 3 weeks after experiencing bilateral lower extremity weakness, lethargy, several falls, hyperthermia, confusion, and gait abnormalities. A CSF analysis demonstrated a lymphocyte pleocytosis with elevated protein and no bacterial or viral growth. The patient was treated with high-dose steroids after which his symptoms resolved. Chest, abdomen, and pelvic CT scans over the next 3 years revealed no evidence of metastatic disease, reflecting a progression-free survival of 40 months. We highlight the unique case of a patient with metastatic RCC who experienced immune-related meningoencephalitis following immunotherapy with nivolumab. Medical oncologists should be alert to the potential development of immune-related encephalitis in patients treated with nivolumab and should promptly diagnose and treat this concerning condition. The excellent oncologic outcome of this case emphasizes the need for continued aggressive measures for management of CNS toxicity resulting from CPI therapy.

Background Ovarian cancer is one of the rarest lethal oncologic diseases that have hardly any specific biomarkers. The availability of high-throughput genomic data and advancement in bioinformatics tools allow us to predict gene biomarkers and apply systems biology approaches to get better diagnosis, and prognosis of the disease with a tentative drug that may be repurposed. Objective To perform genome-wide association studies using microarray gene expression of ovarian cancer and identify gene biomarkers, construction and analyze networks, perform survival analysis, and drug interaction studies for better diagnosis, prognosis, and treatment of ovarian cancer. Method The gene expression profiles of both healthy and serous ovarian cancer epithelial samples were considered. We applied a series of bioinformatics methods and tools, including fold-change statistics for differential expression analysis, DisGeNET and NCBI-Gene databases for gene-disease association mapping, DAVID 6.8 for GO enrichment analysis, GeneMANIA for network construction, Cytoscape 3.8 with its plugins for network visualization, analysis, and module detection, the UALCAN for patient survival analysis, and PubChem, DrugBank and DGIdb for gene-drug interaction. Results We identified 8 seed genes that were subjected for drug-gene interaction studies. Because of over-expression in all the four stages of ovarian cancer, we discern that genes HMGA1 and PSAT1 are potential therapeutic biomarkers for its diagnosis at an early stage (stage I). Our analysis suggests that there are 11 drugs common in the seed genes. However, hypermethylated seed genes HMGA1 and PSAT1 showcased a good interaction affinity with drugs cisplatin, cyclosporin, bisphenol A, progesterone, and sunitinib, and are crucial in the proliferation of ovarian cancer. Conclusion Our study reveals that HMGA1 and PSAT1 can be deployed for initial screening of ovarian cancer and drugs cisplatin, bisphenol A, cyclosporin, progesterone, and sunitinib are effective in curbing the epigenetic alteration.

Although combination therapy is not recommended in patients with gastro–entero–pancreatic (GEP) neuroendocrine tumors (NETs), this strategy is widely used in clinical practice. This network meta-analysis of randomized trials evaluates targeted therapies and somatostatin analogues in GEP-advanced NETs, either alone or in combination, comparing the efficacy of different, single or combined treatment strategies in terms of progression-free survival (PFS). Interventions were grouped as analogs, everolimus, everolimus plus SSAs, sunitinib and placebo. In a secondary analysis, we also assessed the efficacy of individual-specific pharmacological treatments vs placebo or each other. From 83 studies identified, 8 randomized controlled trials were selected, with a total of 1849 patients with either functioning or non-functioning NETs. The analysis confirmed the superiority of all treatments over placebo (HR ranging from 0.34, 95% CI: 0.24–0.37 with the combination of everolimus plus SSAs to 0.42, 0.31–0.57 with the analogs; moderate quality of evidence). On ranking analysis, the combination of everolimus plus SSA (P score = 0.86) and then everolimus alone (P score = 0.65) ranked highest in increasing PFS. On comparative evaluation of different interventions, pasireotide (P score = 0.96) and everolimus + octreotide (P score = 0.82) ranked as the best pharmacological treatment options. Our findings support the use of combination therapy in the treatment of functioning and non-functioning GEP NETs. The role of pasireotide should be explored in selected subgroups of patients. Lastly, the combination of everolimus and octreotide appears promising and should be more widely considered in clinical practice.

T-cell immunotherapy and molecular targeted therapies have become standard-of-care treatments for renal cell carcinoma (RCC). There is a need to develop robust biomarkers that predict patient outcomes to targeted therapies to personalise treatment. In recent years, quantitative analysis of imaging features, termed radiomics, has been used to extract tumour features. This narrative mini review summarises the evidence for radiomics prediction of immunotherapy and molecular targeted therapy outcomes in RCC. Radiomics may predict survival, treatment response, and disease progression in RCC treated with tyrosine kinase inhibitors (eg, sunitinib) and immune checkpoint inhibitors (eg, nivolumab). Further validation is necessary in large-scale studies. PATIENT SUMMARY: We summarise evidence on the ability of features extracted from CT (computed tomography) scans to predict patient outcomes from new treatments for kidney cancer. Although these features can predict treatment outcomes for patients, including survival, treatment response, and cancer progression, further research is necessary before this technology can be applied clinically.

This research investigated a novel folic acid(FA)-modified zirconium core metal-organic framework(MOF) Uio-66 as a nanocarrier to deliver indocyanine green(ICG) and Sunitinib to cancer cells for combination therapy. Platinum-loaded Uio-66 nanoparticles(Pu) were synthesized via a one-pot method, followed by the modification with FA on their surfaces. This afforded FPu that enabled subsequent loading of ICG and Sunitinib to achieve dualmodal cancer therapy. Drug loading/release test and singlet oxygen detection were also conducted in vitro, and the nanoparticles showed considerable drug loading efficiency for both ICG and Sunitinib, coupled with a high singlet oxygen generation rate. Specifically, drug loading and encapsulation efficiency of Sunitinib were 2.30% and 72.67%, while those for ICG were 2.87% and 90.28%, respectively. Additionally, cytotoxicity test on HepG2 human hepatocellular carcinoma cancer cell line revealed that the fully functional nanoparticles possess excellent biocompatibility and as such could be further investigated as a potential drug delivery system for effectual carcinoma cancer treatment.

Background Circulating tumor cells (CTCs) correlate with adverse prognosis in patients with breast, colorectal, lung, and prostate cancer. Little data are available for renal cell carcinoma (RCC). Materials and Methods We designed a multicenter prospective observational study to assess the correlation between CTC counts and progression-free survival (PFS) in patients with metastatic RCC treated with an antiangiogenic tyrosine kinase inhibitor as a first-line regimen; overall survival (OS) and response were secondary objectives. CTC counts were enumerated by the CellSearch system at four time points: day 0 of treatment, day 28, day 56 and then at progression, or at 12 months in the absence of progression. Results One hundred ninety-five eligible patients with a median age of 69 years were treated with sunitinib (77.5%) or pazopanib (21%). At baseline, 46.7% of patients had one or more CTCs per milliliter (range, 1 to 263). Thirty patients had at least three CTCs, with a median PFS of 5.8 versus 15 months in the remaining patients (p = .002; hazard ratio [HR], 1.99), independently of the International Metastatic RCC Database Consortium score at multivariate analysis (HR, 1.91; 95% confidence interval [CI], 1.16–3.14). Patients with at least three CTCs had a shorter estimated OS of 13.8 months versus 52.8 months in those with fewer than three CTCs (p = .003; HR, 1.99; multivariate analysis HR, 1.67; 95% CI, 0.95–2.93). Baseline CTC counts did not correlate with response; neither did having CTC sequencing counts greater than or equal to one, two, three, four, or five. Conclusion We provide prospective evidence that the presence of three or more CTCs at baseline is associated with a significantly shorter PFS and OS in patients with metastatic RCC. Implications for Practice This prospective study evaluated whether the presence of circulating tumor cells (CTCs) in the peripheral blood correlates with activity of first-line tyrosine kinase inhibitors in metastatic renal cell carcinoma (RCC). This study demonstrated that almost half of patients with metastatic RCC have at least one CTC in their blood and that those patients with at least three CTCs are at increased risk of early progressive disease and early death due to RCC. Studies incorporating CTC counts in the prognostic algorithms of metastatic RCC are warranted.

Pancreatic neuroendocrine tumors (PanNETs) are increasingly common. Experts debate whether small tumors should be resected. Tumor destruction via injection of cytotoxic agents could offer a minimal invasive approach to this controversy. We hypothesize that a new drug delivery system comprising chondroitin sulfate (CS) hydrogels loaded with sunitinib (SUN) suppresses tumor growth in PanNET cells. Injectable hydrogels composed of CS modified with methacrylate groups (MA) were fabricated and loaded with SUN. Loading target was either 200 µg (SUN200-G) or 500 µg (SUN500-G) as well as sham hydrogel with no drug loading (SUN0-G). SUN release from hydrogels was monitored in vitro over time and cytotoxicity induced by the released SUN was evaluated using QGP-1 and BON1 PanNET cell lines. QGP-1 xenografts were developed in 35 mice and directly injected with 25 µL of either SUN200-G, SUN500-G, SUN0-G, 100 µL of Sunitinib Malate (SUN-inj), or given 40 mg/kg/day oral sunitinib (SUN-oral). SUN-loaded CSMA hydrogel retained complete in vitro cytotoxicity toward the QGP-1 PanNET and BON-1 PanNET cell lines for 21 days. Mouse xenograft models with QGP-1 PanNETs showed a significant delay in tumor growth in the SUN200/500-G, SUN-inj and SUN-oral groups compared with SUN0-G (p = 0.0014). SUN500-G hydrogels induced significantly more tumor necrosis than SUN0-G (p = 0.04). There was no difference in tumor growth delay between SUN200/500G, SUN-inj, and SUN-oral. This study demonstrates that CSMA hydrogels loaded with SUN suppress PanNETs growth. This drug delivery could approach represents a novel way to treat PanNETs and other neoplasms via intratumoral injection.

Context Immune-checkpoint inhibitors (ICIs) are a mainstay treatment of metastatic renal cell carcinoma (mRCC). As not all patients benefit from ICIs, a biomarker-driven clinical decision-making strategy is desirable. Objective To assess the predictive value of programmed death ligand 1 (PD-L1) in mRCC patients treated with ICIs. Evidence acquisition Multiple databases were searched for articles published up to April 2020 according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement. Studies comparing objective response rate (ORR), complete response rate (CRR), progressive disease rate (PDR), or progression-free survival (PFS) based on tumor PD-L1 status in mRCC patients were eligible. Evidence synthesis Six studies matched our eligibility criteria. Treatment with ICIs was associated with significantly higher ORRs and CRRs, and lower PDRs in patients with PD-L1–positive tumors than in those with PD-L1–negative status (odds ratio [OR] 1.84, 95% confidence interval [CI] 1.48–2.28; OR 3.11, 95% CI 2.04–4.75; and OR 0.43, 95% CI 0.31–0.60, respectively). ICI treatment was associated with significantly better PFS in PD-L1–positive patients than in sunitinib-treated patients (hazard ratio 0.65, 95% CI 0.57–0.74), whereas this was not found in patients with PD-L1–negative tumors. Compared with sunitinib, ICI combination therapy improved ORRs and PFS significantly in PD-L1–positive patients of all examined ICIs. Nivolumab plus ipilimumab had the highest likelihood of providing the highest ORR and longest PFS in PD-L1–positive patients. Conclusions PD-L1 positivity of the tumor is associated with improved ORRs and prolonged PFS in mRCC patients receiving ICI treatment and thus helps identify mRCC patients most likely to benefit from ICI treatment. Patient summary The use of an immune-checkpoint inhibitor for the treatment of metastatic renal cell carcinoma (mRCC) improved oncological outcomes, and the status of programmed death ligand 1 could contribute to guiding patients and clinicians when determining personalized treatment strategies for mRCC.