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The Effects of Neoadjuvant Axitinib on Anthropometric Parameters in Patients With Locally Advanced Non-metastatic Renal Cell Carcinoma.

ABSTRACT: OBJECTIVE:To examine the effect that neoadjuvant axitinib for the treatment of localized renal cell carcinoma has on body compartment composition. MATERIALS AND METHODS:The study was based on a single-institution, single-arm clinical trial that enrolled 24 patients with locally advanced non-metastatic biopsy-proven clear cell renal cell carcinoma. Patients received axitinib orally for up to 12 weeks. Computed tomography scans were completed before the start of treatment, after 7 weeks of treatment and at the completion of 12 weeks of treatment. Patients underwent nephrectomy after axitinib treatment. The primary outcome of the current study was change in body compartment composition. Secondary outcomes included development of new-onset sarcopenia and changes in body weight. RESULTS:A total of 23 patients had a complete set of imaging for evaluation, of which 19 (82.6%) lost weight. Median weight loss was 4.5?kg (P?<.001). Seven patients (30.4%) had sarcopenia before treatment, with an additional 5 (21.7%) developing sarcopenia during treatment. Median decrease in skeletal muscle was 2.9?cm2/m2 (P?<.001), visceral adipose tissue was 4.9?cm2/m2 (P?=?.132), and subcutaneous adipose tissue was 1.0?cm2/m2 (P?=?.043). Ten of the 16 patients (62.5%) without baseline sarcopenia achieved a partial response, whereas only 1 of the 7 patients (14.3%) with baseline pretreatment sarcopenia achieved a partial response (P?=?.069). CONCLUSION:Neoadjuvant axitinib resulted in a decrease in skeletal muscle and subcutaneous adipose tissue, as well as weight loss. Patients with baseline sarcopenia tended to have a lower response rate to neoadjuvant axitinib.

SUBMITTER: Chery L

PROVIDER: S-EPMC5790178 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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The Effects of Neoadjuvant Axitinib on Anthropometric Parameters in Patients With Locally Advanced Non-metastatic Renal Cell Carcinoma.

Chéry Lisly L Borregales Leonardo D LD Fellman Bryan B Urbauer Diana L DL Garg Naveen N Parker Nathan N Katz Matthew H G MHG Wood Christopher G CG Karam Jose A JA

Urology 20170710

<h4>Objective</h4>To examine the effect that neoadjuvant axitinib for the treatment of localized renal cell carcinoma has on body compartment composition.<h4>Materials and methods</h4>The study was based on a single-institution, single-arm clinical trial that enrolled 24 patients with locally advanced non-metastatic biopsy-proven clear cell renal cell carcinoma. Patients received axitinib orally for up to 12 weeks. Computed tomography scans were completed before the start of treatment, after 7 w ...[more]

PMID: 28705573

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Project description:Previous studies have shown a modest impact of tyrosine kinase inhibitors on primary renal tumors. Those studies were mostly retrospective or heterogeneous in their eligibility criteria with regard to histology, disease stage, duration of therapy, and time off therapy prior to surgery.To prospectively investigate the safety and efficacy of axitinib in downsizing tumors in patients with nonmetastatic biopsy-proven clear cell renal cell carcinoma (ccRCC).This was a single-institution, single-arm phase 2 clinical trial. Patients with locally advanced nonmetastatic biopsy-proven ccRCC were eligible.Patients received axitinib 5mg for up to 12 wk. Axitinib was continued until 36h prior to surgery. Patients underwent partial or radical nephrectomy after axitinib therapy.The primary outcome was objective response rate prior to surgery. Secondary outcomes included safety, tolerability, and quality of life. A dedicated radiologist independently reviewed all computed tomography scans to evaluate for response using Response Evaluation Criteria in Solid Tumors (RECIST).A total of 24 patients were treated. Twenty-two patients continued axitinib for 12 wk; 1 patient continued axitinib for 11 wk and underwent surgery as planned. One patient stopped treatment at 7 wk due to adverse events (AEs). Median reduction of primary renal tumor diameter was 28.3%. Eleven patients experienced a partial response per RECIST; 13 had stable disease. There was no progression of disease while on axitinib. The most common AEs were hypertension, fatigue, oral mucositis, hypothyroidism, and hand-foot syndrome. Postoperatively, 2 grade 3 and 13 grade 2 complications were noted. No grade 4 or 5 complications occurred. Functional Assessment of Cancer Therapy-Kidney Specific Index-15 changed over time, with quality of life worsening while on therapy, but by week 19, it was not statistically different from screening. Limitations include single-arm design and small patient numbers.Axitinib was clinically active and reasonably well tolerated in the neoadjuvant setting in patients with locally advanced nonmetastatic ccRCC.In this prospective clinical trial, we found that axitinib, when given prior to surgery, results in significant shrinking of kidney cancers. Larger studies are needed prior to further clinical use.This clinical trial was registered with clinicaltrials.gov (NCT01263769).

Project description:In recent years, targeted agents have changed the treatment landscape for patients with advanced renal cell carcinoma (RCC), greatly improving treatment outcomes. Several targeted agents are now licensed for the treatment of metastatic RCC (mRCC), and a number of new agents are under investigation. Axitinib, a small molecule indazole derivative is an oral, potent multitargeted tyrosine kinase receptor inhibitor, which selectively inhibits vascular endothelial growth factor receptors (VEGFR)-1, -2, and -3 at subnanomolar concentrations, in vitro. In various nonclinical models, axitinib has demonstrated in vivo target modulation and antiangiogenesis. In pharmacokinetic studies, axitinib administered orally with food at the proposed regimen of 5?mg twice daily continuous daily dosing, is rapidly absorbed, reaching peak concentrations within 2-6 hours. Axitinib is metabolized primarily in the liver via the cytochrome P450 (CYP) system with less than 1% of the administered drug passing unchanged in the urine. The pharmacokinetics of axitinib do not appear to be altered by coadministered chemotherapies, and antacids do not have a clinically significant effect. However, coadministration with CYP3A4 and 1A2 inducers is contraindicated. In addition, proton pump inhibitors reduce the rate of axitinib absorption. Increased axitinib exposure is associated with higher efficacy indicated by decreased tumor perfusion and volume. In three phase II clinical trials in patients with advanced RCC previously treated with cytokines, chemotherapy or targeted agents, axitinib has demonstrated antitumor activity with a favorable non-cumulative toxicity profile. In one study of Western patients with cytokine-refractory mRCC, an objective response rate (ORR) of 44.2% (95% CI 30.5, 58.7) was achieved. The median time to progression was 15.7 months (95% CI 8.4, 23.4) and the median overall survival (OS) was 29.9 months (95% CI 20.3, not estimable). In the second study of patients with sorafenib-refractory mRCC, ORR was 22.6% (95% CI 12.9, 35.0). The median progression-free survival (PFS) was 7.4 months (95% CI 6.7, 11.0) and a median OS of 13.6 months (95% CI 8.4, 18.8) was achieved. Results from the third study in Japanese patients with cytokine-refractory mRCC reported an ORR of 55% and median PFS of 12.9 months (95% CI 9.8, 15.6). In the three studies, the most common adverse events reported were fatigue, hypertension, hand-foot syndrome (HFS), and gastrointestinal toxicity, which were generally manageable with standard medical intervention. Of note, the incidence of HFS and proteinuria in the Japanese study was higher than that reported in the Western study in cytokine-refractory mRCC patients. An observed association between diastolic blood pressure ?90?mmHg and increased efficacy suggests potential use as a prognostic biomarker. However, this requires further investigation. Two randomized phase III clinical trials are ongoing to determine the efficacy of axitinib in patients with mRCC in the first- and second-line setting. These results will help to determine the place of axitinib in the mRCC treatment algorithm.

Project description:BackgroundIn a single-group, phase 1b trial, avelumab plus axitinib resulted in objective responses in patients with advanced renal-cell carcinoma. This phase 3 trial involving previously untreated patients with advanced renal-cell carcinoma compared avelumab plus axitinib with the standard-of-care sunitinib.MethodsWe randomly assigned patients in a 1:1 ratio to receive avelumab (10 mg per kilogram of body weight) intravenously every 2 weeks plus axitinib (5 mg) orally twice daily or sunitinib (50 mg) orally once daily for 4 weeks (6-week cycle). The two independent primary end points were progression-free survival and overall survival among patients with programmed death ligand 1 (PD-L1)-positive tumors. A key secondary end point was progression-free survival in the overall population; other end points included objective response and safety.ResultsA total of 886 patients were assigned to receive avelumab plus axitinib (442 patients) or sunitinib (444 patients). Among the 560 patients with PD-L1-positive tumors (63.2%), the median progression-free survival was 13.8 months with avelumab plus axitinib, as compared with 7.2 months with sunitinib (hazard ratio for disease progression or death, 0.61; 95% confidence interval [CI], 0.47 to 0.79; P<0.001); in the overall population, the median progression-free survival was 13.8 months, as compared with 8.4 months (hazard ratio, 0.69; 95% CI, 0.56 to 0.84; P<0.001). Among the patients with PD-L1-positive tumors, the objective response rate was 55.2% with avelumab plus axitinib and 25.5% with sunitinib; at a median follow-up for overall survival of 11.6 months and 10.7 months in the two groups, 37 patients and 44 patients had died, respectively. Adverse events during treatment occurred in 99.5% of patients in the avelumab-plus-axitinib group and in 99.3% of patients in the sunitinib group; these events were grade 3 or higher in 71.2% and 71.5% of the patients in the respective groups.ConclusionsProgression-free survival was significantly longer with avelumab plus axitinib than with sunitinib among patients who received these agents as first-line treatment for advanced renal-cell carcinoma. (Funded by Pfizer and Merck [Darmstadt, Germany]; JAVELIN Renal 101 ClinicalTrials.gov number, NCT02684006.).

Dataset Information

The Effects of Neoadjuvant Axitinib on Anthropometric Parameters in Patients With Locally Advanced Non-metastatic Renal Cell Carcinoma.

Publications

The Effects of Neoadjuvant Axitinib on Anthropometric Parameters in Patients With Locally Advanced Non-metastatic Renal Cell Carcinoma.

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