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Presurgical axitinib therapy increases fibrotic reactions within tumor thrombus in renal cell carcinoma with thrombus extending to the inferior vena cava
Abstract
Background:
Clinical benefits of presurgical axitinib therapy for renal cell carcinoma (RCC) extending into the inferior vena cava (IVC) remain unclear. We aimed to investigate surgical benefits and pathological antitumor effects of presurgical axitinib therapy for RCC with IVC thrombus.
Methods:
Of 56 consecutive RCC patients with IVC thrombus between January 1994 and December 2016, 41 patients who underwent radical nephrectomy (RN) were categorized as upfront RN (Upfront group) or presurgical axitinib followed by RN (Presurgical group). We retrospectively evaluated safety, radiologic tumor responses, and Ki-67 proliferation index before and after axitinib administration in the Presurgical group. Surgical outcomes, postoperative complications, and fibrosis within the IVC thrombus were compared between the Upfront and Presurgical groups.
Results:
The number of patients in the Upfront and Presurgical groups was 31 and 10, respectively. Major presurgical axitinib-related adverse events were grade 2 or 3 hypertension (50%). The median radiological tumor response in the renal tumor, IVC thrombus length, and IVC thrombus volume were -19%, -21 mm, and -54%, respectively. The fibrosis within the IVC thrombus was significantly higher in the Presurgical group (10%) than in the Upfront group (3.4%). The Ki-67 proliferation index was significantly decreased in RN specimens (7.3%) versus needle biopsy specimens (23%) in the Presurgical group. Blood loss and operative duration were significantly lower and shorter, respectively, in the Presurgical group than in the Upfront group.
Conclusions:
Presurgical axitinib therapy enhanced tumor reduction accompanied by fibrosis and may contribute to surgical risk reduction for selected patients.
... Such patients may particularly benefit from neoadjuvant therapy to downstage both the primary tumor and the IVC TT. Retrospective studies have supported this notion, including the study by Tanaka et al. evaluating 41 RCC patients with IVC TT who underwent upfront RN (n = 31) or neoadjuvant axitinib followed by RN (n = 10) [47]. Neoadjuvant axitinib led to a median 21 mm and 54% reduction in IVC TT length and volume, respectively [47]. ...
... Retrospective studies have supported this notion, including the study by Tanaka et al. evaluating 41 RCC patients with IVC TT who underwent upfront RN (n = 31) or neoadjuvant axitinib followed by RN (n = 10) [47]. Neoadjuvant axitinib led to a median 21 mm and 54% reduction in IVC TT length and volume, respectively [47]. Furthermore, the neoadjuvant axitinib group had lower blood loss and shorter operative duration when compared to the upfront RN group [47]. ...
... Neoadjuvant axitinib led to a median 21 mm and 54% reduction in IVC TT length and volume, respectively [47]. Furthermore, the neoadjuvant axitinib group had lower blood loss and shorter operative duration when compared to the upfront RN group [47]. However, other small series of neoadjuvant VEGFR-TKI +/− IO reported modest benefit in terms of IVC TT regression and/or changes in surgical approaches [48][49][50]. ...
The introduction of vascular endothelial growth factor receptor-tyrosine kinases (VEGFR-TKIs) and immune checkpoint inhibitors (IOs) have drastically altered the treatment landscape for kidney cancer, with doublet combination immunotherapy (IO/IO or IO/VEGFR-TKI) now set as the standard front-line treatment for advanced renal cell carcinoma (RCC). However, the roles of VEGFR-TKIs and IOs in the neoadjuvant setting for locoregional/locally advanced RCC remain undefined, where the goals may be primary tumor downsizing/downstaging and potentially eradicating micrometastatic disease. This review will examine VEGFR-TKI monotherapy, IO monotherapy, and VEGFR-TKI/IO combination regimens in a preoperative setting with a focus on the efficacy, toxicity, surgical, and long-term implications.
... There is no Level I or II evidence of pre-surgical targeted therapy in non-metastatic or metastatic RCC VTT. Four retrospective studies focused on mixed groups of vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKI) [5][6][7][8]: sunitinib [9,10], axitinib [11] and pazopanib [12]. VTT level decreased in a median of 22.6% patients (range 14.9-32.9%), ...
... and increased in 7.2% (3.4-14.3%). Results were most favourable for sunitinib and axitinib [5,7,11]. There are several prospective studies on VEGFR TKIs in the pre-nephrectomy setting [13][14][15], but none specifically addresses the question of surgical downstaging of vein-involved local extension. ...
... Interestingly, results from NAXIVA are superior to previous retrospective studies, 37.5% vs 14.9-32.9% reduction in Mayo Levels 1-4 [5][6][7][8][9][10][11][12]. Despite permissive product labels in advanced disease, VEGFR TKIs do appear less active in non-ccRCC [28], and we caution against extrapolation of the findings of NAXIVA to patients in whom there is not pre-treatment histological proof of ccRCC. ...
Background
Surgery for renal cell carcinoma (RCC) with venous tumour thrombus (VTT) extension into the renal vein (RV) and/or inferior vena cava (IVC) has high peri-surgical morbidity/mortality. NAXIVA assessed the response of VTT to axitinib, a potent tyrosine kinase inhibitor.
Methods
NAXIVA was a single-arm, multi-centre, Phase 2 study. In total, 20 patients with resectable clear cell RCC and VTT received upto 8 weeks of pre-surgical axitinib. The primary endpoint was percentage of evaluable patients with VTT improvement by Mayo level on MRI. Secondary endpoints were percentage change in surgical approach and VTT length, response rate (RECISTv1.1) and surgical morbidity.
Results
In all, 35% (7/20) patients with VTT had a reduction in Mayo level with axitinib: 37.5% (6/16) with IVC VTT and 25% (1/4) with RV-only VTT. No patients had an increase in Mayo level. In total, 75% (15/20) of patients had a reduction in VTT length. Overall, 41.2% (7/17) of patients who underwent surgery had less invasive surgery than originally planned. Non-responders exhibited lower baseline microvessel density (CD31), higher Ki67 and exhausted or regulatory T-cell phenotype.
Conclusions
NAXIVA provides the first Level II evidence that axitinib downstages VTT in a significant proportion of patients leading to reduction in the extent of surgery.
Clinical trial registration
NCT03494816.
... The specific information retrieved from each study is shown in Tables Ⅰ and SⅠ. Among the 9 included studies, 3 were randomized controlled trials (19,20,22) and the remaining studies were retrospective, non-randomized studies (21,(23)(24)(25)(26)(27). In the included studies, the patients in the neoadjuvant group had all received the targeted therapy before surgery, and the reported median or average ages of patients ranged from 55.7-71.4 years old. ...
... This aforementioned study provided the first level II evidence that axitinib could downstage VTT in a large proportion of patients and reduce the extent of surgery. Another two studies indicated that preoperative neoadjuvant therapy was beneficial in reducing surgical risk and improving surgical outcomes (23,24). Neoadjuvant therapy may improve venous flow in the IVC via promoting tumor shrinking or thrombus reduction, which could eliminate the fragile collateral venous flow and decrease intraoperative blood loss. ...
To evaluate the effects of neoadjuvant vascular endothelial growth factor-tyrosine kinase inhibitor (VEGF-TKI) treatment on surgery in patients with renal cell carcinoma (RCC), sources from Embase, PubMed and the Cochrane Library databases collected from inception to December, 2022 were used for analysis in the present study, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Data regarding surgical outcomes were collected. The pooled effect sizes were calculated in terms of the risk ratio (RR)/standard mean difference (SMD) with 95% confidence intervals (CIs) using the random-effects model. Subgroup and sensitivity analyses were used to explore the source of heterogeneity within the data. In total, 9 identified articles involving 829 patients (336 in the neoadjuvant + surgery group; 493 in the surgery group) were included in the present study, according to the criteria. The results demonstrated that there were no significant differences in blood loss (SMD=−0.11; 95% CI, −0.63–0.41; P=0.68), postoperative length of hospital stay or total length of hospital stay (SMD=0.23; 95% CI, −0.55–1.01; P=0.57) or complications (RR=1.16; 95% CI, 0.80–1.67; P=0.44) between the two groups. However, neoadjuvant therapy reduced the operation time (SMD=−0.67; 95% CI, −1.25- −0.09; P=0.02) and resulted in a greater proportion of patients choosing partial nephrectomy (RR=1.84; 95% CI, 1.47–2.31; P<0.00001). In the subgroup analysis, the blood loss was significantly lower in patients with RCC with inferior vena cava tumor thrombus in the neoadjuvant group (SMD=−1.10; 95% CI, −1.82- −0.38; P=0.003). In conclusion, the results of the present study indicated that neoadjuvant VEGF-TKI treatment in patients with RCC shortened operation time, decreased blood loss and did not cause an increase in perioperative complications. In addition, this treatment modality may encourage patients to opt for partial nephrectomy to preserve renal function.
... Given that TKI-IO combined regimens have been shown to have a superior effect on primary tumour and metastases than TKI therapy alone [2], there is compelling rationale for future neoadjuvant trials using these agents. Of note, one case series reported longer operative time and higher blood loss following neoadjuvant treatment [5]. This marries with our experience where many patients who have received IOcombined therapy prior to CN have an intense inflammatory reaction or fibrotic tissue, particularly around hilar vessels or the IVC. ...
... Our findings not only provide vital information for mechanistic research, but also reveal novel biomarkers for molecular subtyping or therapeutic decision-making. Several studies have found that targeted therapy achieves satisfactory effects only in a subset of RCC patients 6,20,21 . Fukuda et al. assessed how tumor thrombus height changed following targeted therapy and found that approximately 20% of patients experienced a steady increase in tumor thrombus height throughout treatment 22 . ...
Abstract Clear cell renal cell carcinoma (ccRCC) with venous tumor thrombus (VTT) is associated with poor prognosis. Our integrative analyses of transcriptome and proteome reveal distinctive molecular features of ccRCC with VTT, and yield the development of a prognostic classifier to facilitate ccRCC molecular subtyping and treatment. The RNA sequencing and mass spectrometry were performed in normal-tumor-thrombus tissue triples of five ccRCC patients. Statistical analysis, GO and KEGG enrichment analysis, and protein–protein interaction network construction were used to interpret the transcriptomic and proteomic data. A six-gene-based classifier was developed to predict patients’ survival using Cox regression, which was validated in an independent cohort. Transcriptomic analysis identified 1131 tumorigenesis-associated differentially expressed genes (DEGs) and 856 invasion-associated DEGs. Overexpression of transcription factor EGR2 in VTT indicated its important role in tumor invasion. Furthermore, proteomic analysis showed 597 tumorigenesis-associated differentially expressed proteins (DEPs) and 452 invasion-associated DEPs. The invasion-associated DEPs showed unique enrichment in DNA replication, lysine degradation, and PPAR signaling pathway. Integration of transcriptome and proteome reveals 142 tumorigenesis-associated proteins and 84 invasion-associated proteins displaying changes consistent with corresponding genes in transcriptomic profiling. Based on their different expression patterns among normal-tumor-thrombus triples, RAB25 and GGT5 were supposed to play a consistent role in both tumorigenesis and invasion processes, while SHMT2 and CADM4 might play the opposite roles in tumorigenesis and thrombus invasion. A prognostic classifier consisting of six DEGs (DEPTOR, DPEP1, NAT8, PLOD2, SLC7A5, SUSD2) performed satisfactorily in predicting survival of ccRCC patients (HR = 4.41, P
... 1,2 Although systemic first-line TKI therapy has changed clinical practice, [3][4][5][6][7][8] immediate CN remained among the possible treatment selections based on several retrospective or small studies. [9][10][11][12][13][14][15][16][17][18][19] However, the clinical implication of immediate CN remains inconclusive because a randomized controlled phase 3 noninferiority trial, CAR-MENA, demonstrated that sunitinib alone was not inferior to immediate CN followed by sunitinib, in terms of OS. 20 Conversely, the SURTIME randomized phase 2 trial that compared immediate CN followed by sunitinib versus three presurgical cycles of sunitinib followed by CN (deferred CN) reported significantly longer median OS in the deferred CN arm. 21 Nevertheless, the benefit and the role of immediate or deferred CN remain unclear because of the evidence-practice gap between patients with mRCC selected for CN in clinical trials and those in real-world practice. ...
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Background: We aimed to compare overall survival (OS) between patients with metastatic renal cell carcinoma (mRCC) treated by cytoreductive nephrectomy (CN) and those not treated by CN. Methods: We retrospectively evaluated 278 patients with mRCC treated with first-line tyrosine kinase inhibitors (TKIs) between January 2008 and November 2019. Patients were divided into two groups, CN group (immediate or deferred CN) and systemic TKI therapies alone without CN (Ctrl group). The OS was compared in all patients between the Ctrl and CN groups, between the Ctrl and immediate CN groups, between the Ctrl and deferred CN groups, and between the deferred CN and immediate CN groups. Analyses were weighted using the propensity score–based inverse probability of treatment weighting (IPTW) method to adjust for group imbalances. Results: The median age of the patients was 65 (range 59–73) years. Of the 278 patients, 132 and 146 were in the Ctrl and CN (immediate: 107 and deferred: 39) groups, respectively. A significant difference was noted between the Ctrl and CN groups in age, clinical stage, IMDC risk factors, and the number of metastatic sites. An IPTW-adjusted Cox regression analysis revealed a significant difference in OS between the Ctrl and CN groups and between the Ctrl and immediate or deferred CN groups. However, there was no significant difference in OS between immediate and deferred CN groups. Conclusions: The OS in CN group was significantly longer than that in Ctrl group even after the adjustment of potential selection biases.
... 1,2 Although systemic first-line TKI therapy has changed clinical practice, [3][4][5][6][7][8] immediate CN remained among the possible treatment selections based on several retrospective or small studies. [9][10][11][12][13][14][15][16][17][18][19] However, the clinical implication of immediate CN remains inconclusive because a randomized controlled phase 3 noninferiority trial, CAR-MENA, demonstrated that sunitinib alone was not inferior to immediate CN followed by sunitinib, in terms of OS. 20 Conversely, the SURTIME randomized phase 2 trial that compared immediate CN followed by sunitinib versus three presurgical cycles of sunitinib followed by CN (deferred CN) reported significantly longer median OS in the deferred CN arm. 21 Nevertheless, the benefit and the role of immediate or deferred CN remain unclear because of the evidence-practice gap between patients with mRCC selected for CN in clinical trials and those in real-world practice. ...
Objectives
To compare overall survival between patients with metastatic renal cell carcinoma treated by cytoreductive nephrectomy and those not treated by cytoreductive nephrectomy.
Methods
We retrospectively evaluated 278 patients with metastatic renal cell carcinoma treated with first‐line tyrosine kinase inhibitors between January 2008 and November 2019. Patients were divided into two groups: a cytoreductive nephrectomy group (immediate or deferred cytoreductive nephrectomy) and a group who received systemic tyrosine kinase inhibitor therapies alone without cytoreductive nephrectomy (control group). Overall survival comparisons were made in all patients in the control versus the cytoreductive nephrectomy group, the control versus the immediate cytoreductive nephrectomy group, the control versus the deferred cytoreductive nephrectomy group, and the deferred cytoreductive nephrectomy versus the immediate cytoreductive nephrectomy group. Analyses were weighted using the propensity score‐based inverse probability of treatment weighting method to adjust for group imbalances.
Results
The median (range) age of the patients was 65 (59–73) years. Of the 278 patients, 132 and 146 were in the control group and the cytoreductive nephrectomy (immediate, n = 107 and deferred, n = 39) group, respectively. A significant difference was noted between the control and cytoreductive nephrectomy groups in age, clinical stage, International Metastatic Renal Cell Carcinoma Database Consortium risk factors, and the number of metastatic sites. Inverse probability of treatment weighting‐adjusted Cox regression analysis showed a significant difference in overall survival between the control and the cytoreductive nephrectomy groups and between the control and the immediate or deferred cytoreductive nephrectomy groups. However, there was no significant difference in overall survival between the immediate and the deferred cytoreductive nephrectomy groups.
Conclusions
Our findings suggest that metastatic renal cell carcinoma patients undergoing cytoreductive nephrectomy are more likely to have longer overall survival than those who receive tyrosine kinase inhibitor therapy only.
... However, the risk of blood loss was considered because the left renal vein was markedly swollen to the IVC junction, and the collateral circulation was very developed around the kidney. According to the previous report, in RCC with IVC thrombus, blood loss and operative duration were significantly lower and shorter, respectively, in the pre-surgical axitinib therapy than upfront nephrectomy [17]. Furthermore, CheckMate 214 has shown that nivolumab plus ipilimumab has a higher objective response rate than sunitinib [7]. ...
In recent years, immune checkpoint inhibitors have become the most important drugs for treating renal cell carcinoma. In combination with performing nephrectomies, tyrosine kinase inhibitors have been used as neoadjuvant therapy, as they reduce the size of a primary renal mass and cause the disappearance of metastatic lesions. However, there are only a few reports on immune checkpoint inhibitors as neoadjuvant therapy. Herein, we report a case of renal cell carcinoma with multiple lung metastases and an inferior vena cava tumor thrombus that showed a complete response via radical nephrectomy after nivolumab plus ipilimumab. A 47-year-old man was diagnosed with renal cell carcinoma with multiple lung metastases and inferior vena cava tumor thrombus. After four treatment cycles of nivolumab plus ipilimumab and five cycles of nivolumab, we performed radical nephrectomy and resection of the thrombus tumor by excising a part of the inferior vena cava. The pathological diagnosis had no residual tumor. To our knowledge, this is the first case of complete disappearance of all malignant cells. Immunostaining of the primary renal mass revealed strong positivity for CD4 and CD8. The patient has been followed up without additional treatment for 8 months, but no recurrence has been observed. We suggest the use of nivolumab plus ipilimumab as neoadjuvant therapy. However, physicians should consider the possibilities of immune-related adverse events.
... In recent decades, molecular-targeted therapies have been generally used for treatment of mRCC. [1][2][3][4][5][6][7][8][9][10][11] As prognoses in mRCC have improved, more precise stratifications based on risk factors have been required. In the molecular-targeted therapy era, the IMDC risk classification is a standard riskbased stratification. ...
Objectives:
To evaluate the effect of pretreatment C-reactive protein/albumin ratio and modified Glasgow prognostic score on the prognosis in patients with metastatic renal cell carcinoma.
Methods:
A retrospective study was carried out in 176 patients with metastatic renal cell carcinoma who received first-line tyrosine kinase inhibitors. The effect of adding inflammatory prognostic scores to the International Metastatic Renal Cell Carcinoma Database Consortium model (International Metastatic Renal Cell Carcinoma Database Consortium-C-reactive protein/albumin ratio and International Metastatic Renal Cell Carcinoma Database Consortium-Glasgow prognostic score models) on overall survival was evaluated using receiver operating characteristic curves. The prognostic value of inflammatory prognostic scores (C-reactive protein/albumin ratio-modified Glasgow prognostic score) was tested using the Kaplan-Meier method and Cox proportional regression models.
Results:
Patients were stratified into two groups using the cut-off value of 0.05: C-reactive protein/albumin ratio-low (<0.05) and C-reactive protein/albumin ratio-high (≥0.05). The area under the curve was significantly higher in the International Metastatic Renal Cell Carcinoma Database Consortium-C-reactive protein/albumin ratio model (0.720) than that of the International Metastatic Renal Cell Carcinoma Database Consortium model (0.689) and the International Metastatic Renal Cell Carcinoma Database Consortium-modified Glasgow prognostic score model (0.703). Significant differences were observed in overall survival stratified by the number of risk factors in the International Metastatic Renal Cell Carcinoma Database Consortium-C-reactive protein/albumin ratio risk model between one or two and three or four factors (P < 0.001), and three or four and five or more factors (P = 0.001). For the patients in the International Metastatic Renal Cell Carcinoma Database Consortium intermediate-risk group, overall survival was significantly different between the C-reactive protein/albumin ratio-low and -high groups (P = 0.001), whereas it was not significantly different between the patients with one and two International Metastatic Renal Cell Carcinoma Database Consortium risk factors (P = 0.106).
Conclusion:
The C-reactive protein/albumin ratio is a simple and independent predictor of overall survival in patients with metastatic renal cell carcinoma. The predictive activity was significantly improved in the International Metastatic Renal Cell Carcinoma Database Consortium-C-reactive protein/albumin ratio model compared with the International Metastatic Renal Cell Carcinoma Database Consortium/International Metastatic Renal Cell Carcinoma Database Consortium-modified Glasgow prognostic score models.
... Another retrospective report on Axitinib in 10 pts with IVC thrombus demonstrated an increase in the rate of fibrosis, a decrease in the Ki67 proliferation index within the IVC in the POT group as well as a reduction in the median tumor size and IVC (− 19% and − 54%, respectively). Five pts had IVC thrombus reduction among which four had different surgical procedures [36]. Current evidence is limited and not sufficient to allow amendments in the current recommendations for RCC pts with IVC thrombus. ...
The advent of molecular therapy through targeted kinase inhibitors (TKI) has revolutionized the management of renal cell carcinoma. Although surgical resection remains the cornerstone of any therapeutic plan, an increased risk of morbidity and mortality can be of concern in large and complex bulky tumors. Preoperative therapy with TKIs is hypothesized to facilitate resectability, reduce surgical morbidity and allow nephron-sparing surgery. Many concerns on the safety, efficacy and tolerability of these agents before surgery have halted the progress in this setting. In this paper, we will review the indications and safety of preoperative TKIs in RCC as well as the future approaches.
... Case report 1 1,0 59.0 1 yr NA Cost et al [25] 2011 The USA Case report 25 UA UA UA Sunitinib targeted molecular therapy was continued before surgery Harshman et al [26] 2009 The USA Case report 1 0,1 57.0 UA Sunitinib targeted molecular therapy was continued before surgery Robertae et al [27] 2009 France Case report 1 0,1 78.0 3 mo Sunitinib targeted molecular therapy was continued before surgery Iwamoto et al [28] 2018 Japan Perspective 74 55,19 64.0 (59.8-69.3) 2 yr Give the standard initial dose of sunitinib is 50 mg/d several weeks before surgery Czarnecka et al [1] 2017 Poland Perspective 180 UA 60.5 (25.0-82.0) 2 yr NA Gu et al [18] 2017 China Perspective 17 15,2 50.0 1 yr A 4-week cycle sunitinib taken orally at 50 mg per day for a 6-week cycle (4 wk on treatment, 2 wk off) Fujita et al [29] 2018 Japan Perspective 56 40,16 71.0-80.0 1 yr 50 mg sunitinib was administered orally once daily in a 6-week cycle consisting of 4 wk of treatment followed by 2 wk without treatment Tanaka et al [30] 2018 Japan plus IFN-a treatment in patients with metastatic and advanced RCC, which was deemed as the first-line treatment. [1,33,34] However, the clinical indications to receive second-line treatment and the OS and PFS benefits following first-line treatment should also be further discussed and investigated. ...
Background:
The aim of this systematic review and meta-analysis is to comprehensively evaluate the efficacy and safety of the perioperative use of sunitinib in patients with metastatic and advanced renal cell carcinoma (RCC).
Materials and methods:
We searched authenticated databases for related clinical studies. The baseline characteristics, parameters concerning the efficacy and safety of the perioperative use of sunitinib were extracted for subsequent comprehensive analysis. The parameters which reflected the efficacy and safety as overall survival (OS), progression-free survival (PFS), occurrence rate of all-grade and grade ≥3 adverse effects (AEs) were carefully pooled using comprehensive meta-analysis.
Results:
We finally recruited 411 patients from 14 eligible studies. We found proteinuria (75.0%, 95% CI 62.1%-84.6%), anemia (71.6%, 95% CI 60.9%-80.3%), athesia (60.0%, 95% CI 40.3%-77.0%), pause symptoms (59.2%, 95% CI 49.2%-68.4%), arterial hypertension (53.1%, 95% CI 43.2%-62.7%), and thrombocytopenia (52.5%, 95% CI 44.8%-60.0%) to be the most common all-grade AEs. And arterial hypertension, athesia, cutaneous toxicity, hypophosphatemia, leukopenia, pain, pause syndrome, renal dysfunction, and thrombocytopenia were the most common types of grade ≥3 AEs. In addition, objective response rate (ORR) of sunitinib to both the original and metastatic tumor sites increased with the use of sunitinib, so did the OS and PFS.
Conclusion:
Common all-grade and grade ≥3 AEs were carefully monitored. The perioperative use of sunitinib showed superior ORR, OS, and PFS rates. Nevertheless, more studies are required to further verify these findings.
... In this study, we for the first time compared oncological outcomes and safety of first-line axitinib and sunitinib in patients with treatment-naïve mRCC. A few studies have investigated the efficacy and safety of axitinib as the firstline therapy for mRCC [1,2,15,[24][25][26][27][28]. IPTW-adjusted multivariate analyses revealed that CSS and OS were significantly prolonged in the axitinib group than in the sunitinib group. ...
We aimed to compare oncological outcomes and safety of axitinib and sunitinib in patients with treatment-naïve metastatic renal cell carcinoma (mRCC). We retrospectively evaluated 169 patients with mRCC who were treated with axitinib or sunitinib as the first-line therapy in five hospitals between October 2008 and August 2018. Oncological outcomes and safety were compared between axitinib (n = 68) and sunitinib (n = 101) groups. Inverse probability of treatment weighted (IPTW)-adjusted Cox regression analysis was performed to evaluate effects of first-line therapies on progression-free survival (PFS), cancer-specific survival (CSS), and overall survival (OS). Patients in the axitinib group were significantly older (66 vs. 72 years) than those in the sunitinib group. Median relative dose intensity was significantly higher in the axitinib group (94 ± 62%) than in the sunitinib group (65 ± 20%; P = 0.001). Objective response rate was significantly higher in the axitinib group (21%) than in the sunitinib group (10%; P = 0.042). IPTW-adjusted Cox regression analysis revealed significant differences in CSS and OS but not in PFS between the two groups. Safety in terms of grade ≥ 3 adverse events was significantly different between the axitinib (34%) and sunitinib (55%) groups (P = 0.006). Compared with sunitinib, axitinib significantly prolonged CSS and OS and showed a safer profile as the first-line therapy for treatment-naïve mRCC.
Background/aim:
Surgical treatment of renal cell carcinoma (RCC) with inferior vena cava (IVC) thrombus is associated with high morbidity and mortality rates, therefore presurgical systemic therapies are required in order to improve the safety and feasibility of the surgical procedure by decreasing the thrombus level and burden. The efficacy of presurgical combination therapy of immune checkpoint inhibitors (ICI) and tyrosine kinase inhibitors (TKI) for advanced renal cell carcinoma with IVC thrombus remains unclear.
Case report:
We report a case of a 69-year-old male with cT3bN0M0 locally advanced RCC. We successfully performed a less invasive nephrectomy with thrombectomy, because nivolumab plus cabozantinib administration remarkably reduced the primary tumor and IVC thrombus, resulting in complete pathological response, as assessed with perioperative immunohistochemistry.
Conclusion:
To the best of our knowledge, this is the first report showing that nephrectomy could be safely performed for RCC with IVC thrombus after presurgical nivolumab plus cabozantinib therapy, leading to pathological complete response.
Background:
Malignancies involving the inferior vena cava (IVC) have historically been considered not amendable to surgery. More recently, involvement of the IVC by neoplastic processes in the kidney, liver or in the retroperitoneum can be managed successfully.
Methods:
In this systematic review we summarize the current evidence regarding the surgical management of the IVC in cases of involvement in neoplastic processes. Current literature was searched and studies selected on the base of the PRISMA guidelines. Evidence was synthesized in narrative form due to heterogeneity of studies.
Results:
Renal cell carcinoma accounts for the greatest proportion of studied patients and can be managed with partial or complete vascular exclusion of the IVC, thrombectomy and direct closure or patch repair with good oncological prognosis. Hepatic malignancies or metastases may involve the IVC, and the joint expertise of hepatobiliary and vascular surgeons has developed various strategies, according to the location of tumor and the need to perform a complete vascular exclusion above the hepatic veins. In retroperitoneal lymph node dissection, the IVC can be excised en-block to guarantee better oncological margins. Also, in retroperitoneal sarcomas not arising from the IVC a vascular substitution may be required to improve the overall survival by clearing all the neoplastic cells in the retroperitoneum. Leiomyoma can have a challenging presentation with involvement of the IVC requiring either thrombectomy, partial or complete substitution, with good oncological outcomes.
Conclusions:
A multidisciplinary approach with specialist expertise is required when dealing with IVC involvement in surgical oncology. Multiple techniques and strategies are required to deliver the most efficient care and achieve the best possible overall survival. The main aim of these procedures must be the complete clearance of all neoplastic cells and achievement of a safe margin according to the perioperative treatment strategy.
Background/ Aim: We evaluated surgical outcomes following nephrectomy and thrombectomy with and without presurgical treatment with pazopanib in patients with advanced renal cell carcinoma with inferior vena caval tumor thrombosis.
Materials and methods:
We compared surgical outcomes between patients undergoing presurgical treatment with pazopanib vs. surgery-alone in 19 patients who underwent surgery for advanced renal cell carcinoma with high-level inferior vena caval tumor thrombosis at the Kobe University Hospital.
Results:
Comparing the presurgical group with the surgery-alone group, respectively, the average operative time was 497 min vs. 627 min (p=0.08); average blood loss was 1,928 ml vs. 7,393 ml (p<0.05); average postoperative hospitalization duration was 15.3 days vs. 21.6 days (p=0.05); and the perioperative complication rate was lower (presurgical: 33% vs. surgery-alone: 50%).
Conclusion:
Presurgical treatment with pazopanib decreased surgical difficulty and improved surgical outcomes for advanced renal cell carcinoma with high-level inferior vena caval tumor thrombosis.
Background:
The objective of the study was to validate the characteristics of the International Metastatic Renal-Cell Carcinoma Database Consortium (IMDC) prognostic model in patients treated with first-line axitinib in clinical practice.
Patients and methods:
We retrospectively evaluated 143 patients with metastatic renal-cell carcinoma who were treated with axitinib as the first-line therapy between October 2008 and February 2019. Overall survival (OS) was evaluated according to the IMDC prognostic model. We investigated the intragroup heterogeneity in the intermediate-risk group and divided these patients according to abnormal C-reactive protein (CRP) levels. An inverse probability of treatment-weighted (IPTW)-adjusted Cox regression analysis was performed to evaluate the effects of the CRP-risk model of OS in the patients in the IMDC intermediate-risk group.
Results:
A significant difference in OS was observed in patients in the IMDC intermediate- and poor-risk group, although no significant difference was observed between the IMDC favorable- and intermediate-risk group. Significantly shorter prognosis was observed in patients in the IMDC intermediate-risk group who had 2 risk factors and CRP ≥0.3 mg/dL (inter-high group) than in those with 1 risk factor or 2 risk factors with CRP <0.3 mg/dL (inter-low group). IPTW-adjusted Cox regression analysis revealed significant differences in the OS between the inter-low and inter-high groups.
Conclusion:
The IMDC prognostic model was active in patients who received first-line axitinib treatment. The combination of CRP value with the number of positive risk factors in the IMDC model might predict prognosis in patients with IMDC intermediate-risk treated with first-line axitinib.
Background and objective:
A quantitative tumor response evaluation to molecular-targeting agents in advanced renal cell carcinoma (RCC) is debatable. We aimed to evaluate the relationship between radiologic tumor response and pathological response in patients with advanced RCC who underwent presurgical therapy.
Results:
Of 34 patients, 31 underwent scheduled radical nephrectomy. Presurgical therapy agents included axitinib (n = 26), everolimus (n = 3), sunitinib (n = 1), and axitinib followed by temsirolimus (n = 1). The major presurgical treatment-related adverse event was grade 2 or 3 hypertension (44%). The median radiologic tumor response by RECIST, Choi, and CMER were -19%, -24%, and -49%, respectively. Among the radiologic tumor response tests, CMER showed a higher association with tumor necrosis in surgical specimens than others. Ki67/MIB1 status was significantly decreased in surgical specimens than in biopsy specimens. The magnitude of the slope of the regression line associated with the tumor necrosis percentage was greater in CMER than in Choi and RECIST.
Materials and methods:
Between March 2012 and December 2016, we prospectively enrolled 34 locally advanced and/or metastatic RCC who underwent presurgical molecular-targeting therapy followed by radical nephrectomy. Primary endpoint was comparison of radiologic tumor response among Response Evaluation Criteria in Solid Tumors (RECIST), Choi, and contrast media enhancement reduction (CMER). Secondary endpoint included pathological downstaging, treatment related adverse events, postoperative complications, Ki67/MIB1 status, and tumor necrosis.
Conclusions:
CMER may predict tumor response after presurgical molecular-targeting therapy. Larger prospective studies are needed to develop an optimal tumor response evaluation for molecular-targeting therapy.
To evaluate the clinical and histopathological effects of presurgical treatment with sunitinib on inferior vena cava (IVC) tumor thrombus. Between 2010 and 2014, we treated seven patients with renal cell carcinoma and IVC tumor thrombus presurgically with sunitinib. We retrospectively evaluated primitive tumor size, the level of tumor thrombus according to Novick’s classification, its distance above the renal vein, thrombus diameter at its widest segment, and histopathological change after sunitinib treatment. Three patients were diagnosed histologically. Percutaneous biopsy of the renal mass before sunitinib treatment was performed in two patients. One patient was diagnosed after sunitinib treatment following nephrectomy. The primitive tumors shrank upon sunitinib therapy in four cases; however, although the caval thrombus was downstaged (from level II to I) in one patient, the level of caval thrombus did not change in five patients and increased in one patient (from level III to IV). We evaluated the histopathological effects in two patients. In one patient, the IVC tumor thrombus was mostly replaced with necrotic tissue, but its thrombus level was not downstaged. In the other patient, the IVC tumor thrombus was downstaged, but tumor thrombus was not replaced with necrotic tissue and viable tumor cells remained. Presurgical treatment with sunitinib for renal cell carcinoma with IVC tumor thrombus appears to have limited effect on IVC tumor thrombus, in contrast to its effects on primitive tumor shrinkage. In the absence of evidence of presurgical benefits from prospective studies, this treatment may not be systematically advisable.
Background
Renal cell carcinoma (RCC) with sarcomatoid differentiation is invasive, refractory to treatment, and has a higher mortality. Therefore, systemic therapy is still challenging, and the curative resection of localized or locally advanced RCC with sarcomatoid differentiation is very important. Axitinib is a potent and selective second-generation vascular endothelial growth factor receptor tyrosine kinase inhibitor with improved safety and tolerability. Axitinib is generally recommended as second-line therapy for advanced RCC because the phase III axitinib versus sorafenib in advanced RCC (AXIS) trial demonstrated that it achieved longer progression-free survival than sorafenib in patients with metastatic RCC after failure of an approved first-line regimen.
Methods
We present a 73-year-old man who had a large (13 cm in diameter) right RCC with sarcomatoid differentiation that directly invaded the duodenum and inferior vena cava. The patient presented with gastrointestinal bleeding, was unable to eat solid food, and had become emaciated. Thus, his classification was poor risk with anemia, hypercalcemia, and poor performance status, according to the Memorial Sloan-Kettering Cancer Center criteria. He seemed unlikely to survive if radical nephrectomy, cavotomy with thrombectomy, and pancreatoduodenectomy were performed. To reduce the tumor burden and potential operative complications, we administered axitinib as first-line neoadjuvant therapy.
Results
Six weeks of treatment reduced the tumor burden without causing severe toxicities. Subsequently, radical right nephrectomy, cavotomy with thrombectomy, and pancreatoduodenectomy were performed successfully. The pathological treatment effect of axitinib was grade 2 (two-thirds necrosis). The resected tumor showed a heterogeneous reaction for phosphorylated Akt (Ser-473) by Western blotting and immunohistochemistry, indicating that parts of the tumor were sensitive to axitinib and other parts were not.
Conclusion
Axitinib might be promising as preoperative or neoadjuvant therapy for locally advanced RCC (>cT3b or >cTanyN1).
The authors present the first case report of pre-surgical axitinib treatment on primary renal tumor and vena cava thrombus.
We report the case of a 78-year-old woman with renal cell carcinoma and inferior vena cava tumor thrombus, successfully downstaged
with pre-surgical therapy with axitinib. A significant objective response was observed for tumor size and thrombus. After
initiation of axitinib therapy, computed tomography showed a decrease, from 57 to 51 mm, in the maximal renal tumor diameter.
The tumor thrombus had shortened to 42 mm and had moved to the inferior hepatic vein (Levels 4–3), thereby obviating the need
for thoracotomy. The patient finally accepted surgical treatment. Our case was enabled to perform less surgery for advanced
renal cell carcinoma with tumor thrombus using axitinib as a pre-surgical therapy.
Targeted therapy with tyrosine kinase inhibitors has been shown to reduce tumor volumes and prolong the survival of patients with metastatic renal cell carcinoma. Tyrosine kinase inhibitors, particularly sunitinib, have recently been used in neoadjuvant and presurgical settings. Axitinib is a promising second-line therapy option for advanced or metastatic renal cell carcinoma. Herein, we report a patient with advanced renal cell carcinoma who received presurgical treatment with axitinib.
A 73-year-old man was transported by ambulance to a community hospital with chief complaints of high fever and a gait disorder. Computed tomography screening revealed a hypervascular tumor (size, 9 x 8.5 cm) in the lower pole of the left kidney. Upon admission to our hospital, his general condition was poor and his performance status was judged as 3, based on the Eastern Cooperative Oncology Group performance status criteria. After biopsy for the renal tumor, he received 5 mg of axitinib twice daily for 3 months. No serious adverse events were reported during this treatment. The tumor diameter shrank by 56%. Left radical nephrectomy was performed, and there were no intraoperative or postoperative complications. Pathological examination indicated a pT3aN0M0, Furman grade 3, clear cell renal cell carcinoma with necrosis, hyaline degeneration, and hemosiderosis. The patient was asymptomatic and disease-free at 1 year post-diagnosis.
This case study demonstrate that presurgical therapy with axitinib is feasible and might have several potential advantages for patients with advanced renal cell carcinoma.
Management of renal cell carcinoma (RCC) with tumor thrombus extending to the renal vein and inferior vena cava (IVC) is challenging. The aim of this study was to evaluate the benefit of surgical management in such patients.
From February 1995 to February 2013, 520 patients were treated for RCC at Hirosaki University Hospital, Hirosaki, Japan. The RCC patients with tumor thrombus extending to the renal vein (n = 42) and IVC (n = 43) were included in this study. The records of these 85 patients were retrospectively reviewed to assess the relevant clinical and pathological variables and survival. Prognostic factors were identified by multivariate analysis. The benefit of surgical management was evaluated using propensity score matching to compare overall survival between patients who received surgical management and those who did not.
RCC was confirmed by pathological examination of surgical or biopsy specimens in 74 of the 85 patients (87%). Sixty-five patients (76%) received surgical management (radical nephrectomy with thrombectomy). Distant metastasis was identified in 45 patients (53%). The proportion of patients with tumor thrombus level 0 (renal vein only), I, II, III, and IV was 49%, 13%, 18%, 14%, and 5%, respectively. The estimated 5-year overall survival rate was 70% in patients with thrombus extending to the renal vein and 23% in patients with thrombus extending to the IVC. Multivariate analysis identified thrombus extending to the IVC, presence of distant metastasis, surgical management, serum albumin concentration, serum choline esterase concentration, neutrophil-lymphocyte ratio, and Carlson comorbidity index as independent prognostic factors. In propensity score-matched patients, overall survival was significantly longer in those who received surgical management than those who did not.
Surgical management may improve the prognosis of RCC patients with thrombus extending to the renal vein and IVC.
Objective:
To assess the effect of neoadjuvant targeted molecular therapies (TMTs) on size and level of inferior vena cava tumor thrombi and to evaluate their impact on surgical management.
Methods:
We retrospectively analyzed the data of 14 patients treated for a clear cell renal cell carcinoma with inferior vena cava thrombi by neoadjuvant TMT before nephrectomy. Clinical, pathological and perioperative data were gathered retrospectively at each institution. The primitive tumor size and the thrombus size were defined by computed tomography before TMT. The tumor thrombus level was defined according to the Novick's classification.
Results:
Before TMT, thrombus level was staged I for 1 (7%), II for 10 (72%) and III (21%) for 3 patients. First-line therapy was sunitinib in 11 cases and sorafenib in 3 cases. Median therapy duration was two cycles (1-5). Three patients experienced major adverse effects (grade III) during TMT. Following TMT, 6 (43%) patients had a measurable decrease, 6 (43%) had no change, and 2 (14%) had an increase in the thrombus. One patient (7%) had a downstage of thrombus level, 12 (85%) had stable thrombi, and 1 (7%) had an upstage. Regarding primary tumor, 7 (50%), 5 (36%) and 2 (14%) patients had a decrease, stabilization and an increase in tumor size, respectively.
Conclusion:
Neoadjuvant TMT appears to have limited effects on renal tumor thrombi. This retrospective study failed to demonstrate a significant impact of neoadjuvant TMT on surgical management of clear cell renal cell carcinoma with inferior vena cava tumor thrombi.
We retrospectively analyzed our patients with advanced renal cell carcinoma who underwent presurgical targeted therapy with tyrosine kinase inhibitors to clarify the safety and clinical benefit. The histopathological effect of this treatment was also examined.
Between July 2005 and February 2010, nine patients with advanced renal cell carcinoma who were treated with tyrosine kinase inhibitors before surgery were the subjects of this study. Consolidative surgery was considered when these tumors showed clinical response or stable disease while on targeted therapy without evidence of disease progression at other sites.
The agents used were sorafenib in seven patients and sunitinib in two. The median duration of presurgical therapy was 12.2 weeks, and seven patients had less than 4 months of treatment. Tumor reduction at 10-30% was obtained in all patients but one. Perioperative complications were observed in five of nine patients. Major complications occurred in two patients, including intraoperative excessive bleeding and delayed localized intraperitoneal abscess. Minor complications were found in three. The characteristics of the histopathological effect of tyrosine kinase inhibitors consisted of marked atrophy of the capillary sinus, confirming the pharmacological mechanisms of these agents. Other findings included nuclear pyknosis and degeneration of tumor cells.
Presurgical targeted therapy with tyrosine kinase inhibitors appears to be feasible in most patients with advanced renal cell carcinoma. However, the indications, the clinical benefit and the standard protocol still remain to be determined. Therapeutic effects in the histology were compatible to their pharmacological effects.
The incidence of renal cell carcinoma is increasing, with up to one-third of patients presenting with metastatic disease. Combination therapy is used to prolong survival in patients with metastatic renal cell carcinoma, which carries a poor prognosis. Although two pivotal phase 3 trials have demonstrated the efficacy of immunotherapy after cytoreductive nephrectomy for metastatic disease, for now, targeted therapy has replaced immunotherapy as the preferred systemic treatment in these patients. Two ongoing phase 3 trials are evaluating the role of cytoreductive nephrectomy prior to targeted therapy. Proper patient selection is paramount in achieving successful outcomes. © 2016, Millennium Medical Publishing, Inc. All rights reserved.
Ureter tumor thrombus (TT) of renal cell carcinoma (RCC) is quite rare, although RCC-TT in the inferior vena cava (IVC) is not uncommon. We report the first case of RCC-TT extending into the IVC and ovarian vein as well as the ureter. Neoadjuvant axitinib shrank both the primary tumor and TT, making radical nephrectomy less invasive, particularly by down-leveling the IVC-TT. Pathological examination of the primary tumor, IVC-TT, and ureter TT showed clear cell carcinoma with extensive necrosis. Although the role of neoadjuvant axitinib in RCC remains unclear, the present case suggests neoadjuvant axitinib is clinically beneficial for RCC-TT.
Preservation of renal function is prioritized during surgical management of localized RCC. VEGF-targeted agents can downsize tumors in metastatic RCC, and may do the same in localized RCC, allowing for optimal preservation of renal parenchyma associated with partial nephrectomy (PN).
Localized clear cell RCC patients meeting one or both of the following criteria were enrolled in a prospective phase II trial: radical nephrectomy or PN likely to yield GFR<30mL/min/1.73m(2); or PN high risk due to high complexity (RENAL=10-12) or tumor adjacent to hilar vessels. Pazopanib (800mg QD) was administered for 8-16 weeks with repeat imaging at completion of therapy, followed by surgery.
Twenty-five patients enrolled with median tumor size 7.3cm and median RENAL score of 11; 80% of index lesions were high complexity, and 56% of patients had a solitary kidney. Patients received a median 8 weeks of pazopanib; median interval from treatment start to surgery was 10.6 weeks. RENAL score decreased in 71% of tumors and 92% of patients experienced reduction in tumor volume. Six of thirteen patients for whom PN was not possible at baseline were able to undergo PN after treatment. The mean parenchymal volume that could be saved with surgery increased from estimated 107cc to 173cc(p=0.0015). Five patients developed urine leak managed conservatively, and 7 received a transfusion, one of whom required embolization.
Neoadjuvant pazopanib resulted in downsizing of localized RCC, allowing improved preservation of renal parenchyma, and enabling PN in a select subset of patients who would otherwise require radical nephrectomy.
Copyright © 2015 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.
Background
Previous studies have shown a modest impact of tyrosine kinase inhibitors on primary renal tumors. Those studies were mostly retrospective and heterogeneous in their eligibility criteria with regard to histology, disease stage, duration of therapy, and time off therapy prior to surgery.
Objective
To prospectively investigate the safety and efficacy of axitinib in downsizing tumors in patients with nonmetastatic biopsy-proven clear cell renal cell carcinoma (ccRCC).
Design, setting, and participants
This was a single-institution, single-arm phase 2 clinical trial. Patients with locally advanced nonmetastatic biopsy-proven ccRCC were eligible.
Intervention
Patients received axitinib 5 mg for up to 12 wk. Axitinib was continued until 36 h prior to surgery. Patient underwent partial or radical nephrectomy after axitinib therapy.
Outcome measurements and statistical analysis
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).
Results and limitations
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.
Conclusions
Axitinib was clinically active and reasonably well tolerated in the neoadjuvant setting in patients with locally advanced nonmetastatic ccRCC.
Patient summary
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.
Trial registration
This clinical trial was registered with clinicaltrials.gov (NCT01263769).
In previous clinical trials of patients with metastatic renal-cell carcinoma, patients treated with axitinib as second-line therapy had longer median progression-free survival than those treated with sorafenib. We therefore undertook a phase 3 trial comparing axitinib with sorafenib in patients with treatment-naive metastatic renal-cell carcinoma.
In this randomised, open-label, phase 3 trial, patients with treatment-naive, measurable, clear-cell metastatic renal-cell carcinoma from 13 countries were stratified by Eastern Cooperative Oncology Group performance status, and then randomly assigned (2:1) by a centralised registration system to receive axitinib 5 mg twice daily, or sorafenib 400 mg twice daily. The primary endpoint was progression-free survival, assessed by masked independent review committee in the intention-to-treat population. This ongoing trial is registered at ClinicalTrials.gov, NCT00920816.
Between June 14, 2010, and April 21, 2011, we randomly assigned 192 patients to receive axitinib, and 96 patients to receive sorafenib. The cutoff date for this analysis was July 27, 2012, when 171 (59%) of 288 patients died or had disease progression, as assessed by the independent review committee. There was no significant difference in median progression-free survival between patients treated with axitinib or sorafenib (10·1 months [95% CI 7·2-12·1] vs 6·5 months [4·7-8·3], respectively; stratified hazard ratio 0·77, 95% CI 0·56-1·05). Any-grade adverse events that were more common (≥10% difference) with axitinib than with sorafenib were diarrhoea (94 [50%] of 189 patients vs 38 [40%] of 96 patients), hypertension (92 [49%] vs 28 [29%]), weight decrease (69 [37%] vs 23 [24%]), decreased appetite (54 [29%] vs 18 [19%]), dysphonia (44 [23%] vs ten [10%]), hypothyroidism (39 [21%] vs seven [7%]), and upper abdominal pain (31 [16%] vs six [6%]); those more common with sorafenib than with axitinib included palmar-plantar erythrodysaesthesia (PPE; 37 [39%] of 96 patients vs 50 [26%] of 189), rash (19 [20%] vs 18 [10%]), alopecia (18 [19%] vs eight [4%]), and erythema (18 [19%] vs five [3%]). The most common grade 3 or 4 adverse events in patients treated with axitinib included hypertension (26 [14%] of 189 patients), diarrhoea (17 [9%]), asthenia (16 [8%]), weight decrease (16 [8%]), and PPE (14 [7%]); common grade 3 or 4 adverse events in patients treated with sorafenib included PPE (15 [16%] of 96 patients), diarrhoea (five [5%]), and asthenia (five [5%]). Serious adverse events were reported in 64 (34%) of 189 patients receiving axitinib, and 24 (25%) of 96 patients receiving sorafenib.
Axitinib did not significantly increase progression-free survival in patients with treatment-naive metastatic renal-cell carcinoma compared with those treated with sorafenib, but did demonstrate clinical activity and an acceptable safety profile.
Pfizer Inc.
The study was carried out to evaluate the effectiveness, toxicity and optimal duration of neoadjuvant therapy for patients with organ-confined or locally advanced renal cell carcinoma in the era of targeted agents. A literature review was carried out using Medline/Pubmed articles, as well as congress reports from the last five American Society of Clinical Oncology, American Urological Association and European Association of Urology Annual Meetings. Neoadjuvant targeted therapy is feasible and shows toxicity similar to that seen in a palliative setting. Most studies recommend an application for 2-4 months. The current data situation is best for sunitinib. Surgery can apparently be carried out the day right after discontinuing the drug. However, even sunitinib leads to only a mean 10% decrease in primary tumor size, and one-quarter to one-fifth of all patients show local tumor progression during treatment. Few patients (approximately 12%) with a vena cava tumor thrombus achieve a significant decrease in its level under neoadjuvant therapy; here too, progression is observed in a significant number of cases. Even the new targeted agents show limited effectiveness in achieving relevant remissions of the primary tumor. Furthermore, tumor progression is seen in a significant percentage of patients during neoadjuvant therapy. Thus, even today in the era of targeted agents, a neoadjuvant approach should only be made in patients with localized or locally advanced renal cell carcinoma, which primarily seem to be absolutely inaccessible by (partial) nephrectomy.
We investigated the effect of sunitinib on locally advanced primary renal carcinoma tumors and the ability to facilitate subsequent surgery.
Patients with an unresectable primary renal tumor, with or without distant metastases, received 50 mg sunitinib with continuous daily dosing in a phase II trial. Computerized tomography was performed every 12 weeks to determine surgical resectability. The primary end point of the trial was the percentage of patients with renal cell carcinoma and initially unresectable primary tumors who could undergo nephrectomy after sunitinib therapy.
Of 30 patients enrolled in the study (19 with distant metastases) 28 (35 total renal tumors) were evaluable for response. The median change in primary renal cell carcinoma tumors was a 22% decrease, corresponding to a median absolute reduction of 1.2 cm. The median reduction in primary renal cell carcinoma tumors of clear cell histology was -28% (absolute reduction 1.7 cm) compared to a 1.4% increase (0.1 cm absolute increase) in nonclear cell tumors. Of these patients 13 (45%) met the primary end point of being able to undergo nephrectomy after preoperative sunitinib. All patients had viable renal cell carcinoma in the surgical specimen and surgical morbidity was consistent with prior experience of nephrectomy in patients without preoperative therapy.
Sunitinib as initial therapy in patients with locally advanced features of the primary tumor was feasible and resulted in an antitumor effect that enabled subsequent surgery in a subset of patients. Further prospective study is required to refine the most suitable application of this approach.
Targeted molecular therapies (TMTs) previously have demonstrated oncologic activity in renal cell carcinoma (RCC) by reducing the size of primary tumors and metastases.
To assess the cytoreductive effect of TMTs on inferior vena cava tumor thrombi.
A multi-institutional database of patients treated with TMTs for RCC was reviewed. The subset with in situ level II or higher caval thrombi (above renal vein) was assessed for radiographic response in thrombus size and level. Pre- and posttreatment characteristics of this population were assessed for predictors of response in height, diameter, and level of the tumor thrombi.
The main outcome measured was a change in the clinical level of tumor thrombus following TMT. We also measured radiographic responses in thrombus size and location before and after TMT.
Twenty-five patients met the inclusion criteria. Before TMT, thrombus level was II in 18 patients (72%), III in 5 patients (20%), and IV in 2 patients (8%). The first-line therapy was sunitinib in 12 cases; alternative TMTs were administered in 13. The median duration of therapy was two cycles (range: one to six cycles). Following TMT, 7 patients (28%) had a measurable increase in thrombus height, 7 (28%) had no change, and 11 (44%) had a decrease. One patient (4%) had an increase in thrombus-level classification, 21 (84%) had stable thrombi, and in 3 (12%) the thrombus level decreased. There was only one case (4%) where the surgical approach was potentially affected by tumor thrombus regression (level IV to III). No statistically significant predictors of tumor thrombus response to TMTs were found. Limitations include the descriptive and retrospective study design. Because TMTs were initiated according to physician and/or patient preferences, and not all patients were treated in anticipation of surgery, no conclusions could be drawn regarding selection and duration of therapy. Thus it may not be appropriate to extrapolate our experience to all patients with locally advanced RCC. Although this is the largest reported experience with in situ caval tumor thrombi treated with TMT, this series lacks sufficient statistical power to assess the usefulness of TMTs adequately in tumor thrombus cytoreduction.
TMT had a minimal clinical effect on RCC tumor thrombi. Only patients treated with sunitinib had clinical thrombus regression; however, the clinical magnitude and relevance of this effect is not clear and should be investigated prospectively.
The multitargeted tyrosine kinase inhibitor sorafenib is used for the treatment of advanced-stage renal cell carcinoma. However, the safety and efficacy of this agent have yet to be evaluated in the preoperative period, where there may be potential advantages including tumor downstaging. This prospective trial evaluates the safety and feasibility of sorafenib in the preoperative setting.
Thirty patients with clinical stage II or higher renal masses, selected based on their candidacy for nephrectomy, underwent preoperative treatment with sorafenib. Toxicities, surgical complications, and tumor responses were monitored.
Of the thirty patients enrolled, 17 patients had localized disease and 13 had metastatic disease. After a course of sorafenib therapy (median duration, 33 days), a decrease in primary tumor size (median, 9.6%) and radiographic evidence of loss of intratumoral enhancement, quantified using a methodology similar to Choi criteria (median, 13%), was also observed. According to Response Evaluation Criteria in Solid Tumors, of the 28 patients evaluable for response, two patients had a partial response and 26 had stable disease, with no patients progressing on therapy. Toxicities from sorafenib were similar to that expected with this class of medication. All patients were able to proceed with nephrectomy and no surgical complications related to sorafenib administration were observed.
The administration of preoperative sorafenib therapy can impact the size and density of the primary tumor and appears safe and feasible. Further studies are required to determine if preoperative systemic therapy improves outcomes in patients undergoing nephrectomy for renal cell carcinoma.
We assessed the activity of neoadjuvant sunitinib on primary renal tumors in patients with advanced renal cell carcinoma as well as the feasibility and safety of subsequent surgical resection.
A total of 19 patients with advanced renal cell carcinoma deemed unsuitable for initial nephrectomy due to locally advanced disease or extensive metastatic burden were treated with 50 mg sunitinib daily for 4 weeks on followed by 2 weeks off. Tumor response was assessed by Response Evaluation Criteria in Solid Tumors every 2 cycles and the rate of conversion to resectable status was estimated.
Median patient age was 64 years and initial median radiographic renal tumor size was 10.5 cm. Clinical stage was N+ (10) and M+ (15). No patients experienced a complete response. Partial responses of the primary tumor were noted in 3 patients (16%), 7 (37%) had stable disease and 9 (47%) had disease progression in the primary tumor. Overall tumor response included 2 patients (11%) with partial response, 7 (37%) with stable disease and 10 (53%) with disease progression. At a median followup of 6 months (range 1 to 15) 4 patients (21%) had undergone nephrectomy and 5 died of disease progression. No unexpected surgical morbidity was encountered. Viable tumor was present in all 4 specimens. Sunitinib was associated with grade 3-4 toxicity in 7 patients (37%) and treatment was discontinued in 1 due to toxicity.
Administration of sunitinib in patients with advanced renal cell carcinoma with the primary tumor in place is feasible and can lead to a reduction in tumor burden that can facilitate subsequent surgical resection.
The basic objective of this paper is to evaluate an age-comorbidity index in a cohort of patients who were originally enrolled in a prospective study to identify risk factors for peri-operative complications. Two-hundred and twenty-six patients were enrolled in the study. The participants were patients with hypertension or diabetes who underwent elective surgery between 1982 and 1985 and who survived to discharge. Two-hundred and eighteen patients survived until discharge. These patients were followed for at least five years post-operatively. The estimated relative risk of death for each comorbidity rank was 1.4 and for each decade of age was 1.4. When age and comorbidity were modelled as a combined age-comorbidity score, the estimated relative risk for each combined age-comorbidity unit was 1.45. Thus, the estimated relative risk of death from an increase of one in the comorbidity score proved approximately equal to that from an additional decade of age. The combined age-comorbidity score may be useful in some longitudinal studies to estimate relative risk of death from prognostic clinical covariates.