-
1.
Is Axitinib Still a Valid Option for mRCC in the Second-Line Setting? Prognostic Factor Analyses From the AXIS Trial.
Bracarda, S, Bamias, A, Casper, J, Negrier, S, Sella, A, Staehler, M, Tarazi, J, Felici, A, Rosbrook, B, Jardinaud-Lopez, M, et al
Clinical genitourinary cancer. 2019;(3):e689-e703
-
-
Free full text
-
Abstract
BACKGROUND Axitinib resulted in significantly longer progression-free survival (PFS) versus sorafenib in patients with metastatic renal-cell carcinoma (mRCC) previously treated with sunitinib in the AXIS trial. We report post hoc analyses evaluating patient subgroups that may benefit more from axitinib in this setting. PATIENTS AND METHODS AXIS was an open-label randomized phase 3 trial (NCT00678392) in mRCC patients with disease that failed to respond to one prior systemic therapy. Univariate and multivariate analyses evaluated potential prognostic factors for improved PFS and overall survival (OS) after sunitinib. PFS and OS of axitinib versus sorafenib were assessed within subgroups identified according to these factors. RESULTS Of 723 patients, 389 received first-line sunitinib; 194 and 195 were randomized to second-line axitinib and sorafenib, respectively. Identified prognostic factors were: nonbulky disease (sum of the longest diameter < 98 mm), favorable/intermediate risk disease (Memorial Sloan Kettering Cancer Center or International Metastatic Renal Cell Carcinoma Database Consortium criteria), and no bone or liver metastases. In patients with all of these prognostic factors (n = 86), significantly longer PFS was observed for axitinib versus sorafenib (hazard ratio = 0.476; 95% confidence interval, 0.263-0.863; 2-sided P = .0126). OS (hazard ratio = 0.902; 95% confidence interval, 0.457-1.780; 2-sided P = .7661) was similar between treatments. Across subgroups, PFS was generally longer in patients treated with axitinib versus sorafenib, and OS was generally similar between the two treatments. CONCLUSION In patients with mRCC, axitinib remains a suitable second-line treatment option across multiple subgroups. A relevant reduction in the risk of a PFS event was observed for axitinib compared to sorafenib in selected subgroups of patients.
-
2.
High fat mass associates with occurrence of targeted therapy-induced left ventricular ejection fraction reduction in patients with renal cell carcinoma.
Kazemi-Bajestani, SMR, Becher, H, Venner, P, North, S, Baracos, V
Clinical nutrition (Edinburgh, Scotland). 2018;(3):1070-1072
Abstract
BACKGROUND & AIMS Recent research suggests that variations of skeletal muscle (SM) and fat predict the severity of chemotherapy-induced toxicities in patients with renal cell carcinoma (RCC). Cardio-toxicity has not been evaluated in this context. METHODS In this study we considered 47 RCC patients who participated in randomized clinical trials of sorafenib or sunitinib (i.e., targeted therapy). To capture cardio-toxicity, multi gated acquisition (MUGA) scan-defined left ventricular ejection fraction (LVEF) tests (at least 3 tests over 1 year of treatment) were abstracted. Computed tomography (CT) cross-sectional images were analyzed before start of targeted therapy and at 1 year to define SM and fat at baseline and changes over time concurrent with MUGA-defined LVEF measurement. RESULTS MUGA-defined cardio-toxicity (usually fall in LVEF >10% to an absolute LVEF<55%) occurred in 8/47 (17%) patients over 1 year of targeted therapy (all were male). Percentage of patients with high fat mass (baseline CT-defined total adipose tissue/indexed by height2 greater than the gender-specific median value) was higher among patients with cardio-toxicity versus patients without cardio-toxicity [7 (87.5%) versus 16 (41.0%); p = 0.02]. The percentage of SM loss in patients with cardio-toxicity was higher than the patients without cardio-toxicity [median of loss (%) -7 versus 0 respectively; p = 0.04]. CONCLUSION Cardio-toxicity in RCC patients might be associated with high fat mass. This finding is distinct from prior observations that low body weight and sarcopenia associated with non-cardiac toxicities of targeted therapies. Concurrence of SM loss over time and development of cardio-toxicity is reported for the first time.
-
3.
Axitinib Versus Sorafenib in First-Line Metastatic Renal Cell Carcinoma: Overall Survival From a Randomized Phase III Trial.
Hutson, TE, Al-Shukri, S, Stus, VP, Lipatov, ON, Shparyk, Y, Bair, AH, Rosbrook, B, Andrews, GI, Vogelzang, NJ
Clinical genitourinary cancer. 2017;(1):72-76
Abstract
BACKGROUND In a randomized phase III trial in treatment-naive patients with metastatic renal cell carcinoma (RCC), axitinib versus sorafenib yielded numerically longer progression-free survival (median, 10.1 vs. 6.5 months; hazard ratio [HR], 0.77; 1-sided P = .038) and significantly higher objective response rate (32% vs. 15%; 1-sided P = .0006). In this article, we report overall survival (OS) and updated safety results. PATIENTS AND METHODS Previously untreated patients with metastatic RCC (n = 288), stratified according to Eastern Cooperative Oncology Group performance status (ECOG PS; 0 vs. 1), were randomized 2:1 to receive axitinib 5 mg twice per day (b.i.d.; n = 192) or sorafenib 400 mg b.i.d. (n = 96). RESULTS Median OS (95% confidence interval [CI]) was 21.7 months (18.0-31.7) with axitinib versus 23.3 months (18.1-33.2) with sorafenib (stratified HR, 0.995; 95% CI, 0.731-1.356; 1-sided P = .4883). Among patients with ECOG PS of 0, median OS was numerically longer with axitinib than with sorafenib (41.2 vs. 31.9 months; HR, 0.811, 1-sided P = .1748), whereas among patients with ECOG PS 1, median OS was shorter with axitinib than with sorafenib (14.2 vs. 19.8 months; HR, 1.203; 1-sided; P = .7973). Incidence and severity of common adverse events were consistent with previous reports. CONCLUSION OS was similar between axitinib and sorafenib in treatment-naive patients with metastatic RCC, and no new safety signals emerged.
-
4.
Effects of Adjuvant Sorafenib and Sunitinib on Cardiac Function in Renal Cell Carcinoma Patients without Overt Metastases: Results from ASSURE, ECOG 2805.
Haas, NB, Manola, J, Ky, B, Flaherty, KT, Uzzo, RG, Kane, CJ, Jewett, M, Wood, L, Wood, CG, Atkins, MB, et al
Clinical cancer research : an official journal of the American Association for Cancer Research. 2015;(18):4048-54
-
-
Free full text
-
Abstract
PURPOSE Sunitinib and sorafenib are used widely in the treatment of renal cell carcinoma (RCC). These agents are associated with a significant incidence of cardiovascular (CV) dysfunction and left ventricular ejection fraction (LVEF) declines, observed largely in the metastatic setting. However, in the adjuvant population, the CV effects of these agents remain unknown. We prospectively defined the incidence of cardiotoxicity among resected, high-risk RCC patients treated with these agents. EXPERIMENTAL DESIGN Sunitinib, sorafenib, or placebo was administered for up to 12 months in patients with high-risk, resected RCC. LVEF was measured by multigated acquisition (MUGA) scans at standard intervals. Additional CV adverse events were reported according to NCI Common Terminology Criteria for Adverse Events (CTCAE). RESULTS Among 1,943 patients randomized, 1,599 had at least 1 post-baseline MUGA. Within 6 months, 21 patients (1.3%) experienced a cardiac event, defined as an LVEF decline from baseline that was >15% and below the institutional lower limit of normal. Nine of 513 patients (1.8%) were on sunitinib, 7 of 508 (1.4%) on sorafenib, and 5 of 578 (0.9%) on placebo (P = 0.28 and 0.56 comparing sunitinib and sorafenib to placebo, respectively). With dose interruption or adjustment, 16 of the 21 recovered their LVEF to >50%. The incidence of symptomatic heart failure, arrhythmia, or myocardial ischemia did not differ among groups. CONCLUSIONS In the adjuvant setting, we prospectively define low incidence of cardiotoxicity with sunitinib and sorafenib. These findings may be related to close CV monitoring, or potentially to fewer CV comorbidities in our nonmetastatic population.
-
5.
A Prospective Randomized Study of Pfannenstiel Versus Expanded Port Site Incision for Intact Specimen Extraction in Laparoscopic Radical Nephrectomy.
Binsaleh, S, Madbouly, K, Matsumoto, ED, Kapoor, A
Journal of endourology. 2015;(8):913-8
Abstract
PURPOSE To compare intra- and postoperative outcome of patients undergoing laparoscopic radical nephrectomy with intact specimen extraction through a Pfannenstiel (PFN) transverse suprapubic or expanded port site (EPS) incision in a prospective randomized fashion. PATIENTS AND METHODS Patients undergoing laparoscopic transperitoneal radical nephrectomies for suspected renal tumors were randomized for intact renal specimen extraction via a PFN or EPS incision. Operative, perioperative, 1 week, 6 weeks, and 6 months postoperative parameters were prospectively recorded and analyzed including specimen weight, size in maximum diameter, incision length, total operative time, extraction time, estimated blood loss, length of hospital stay, pain score in the postoperative holding area and on the first post operative day, narcotic consumption, time to fluid intake/full diet intake, unassisted ambulation, cosmesis, and wound-related complications. A postoperative quality-of-life questionnaire was also filled out by all the patients. RESULTS Our series included 51 patients: 26 in the PFN group and 25 in the EPS group. The two groups were similar in demographic characteristics and intraoperative and postoperative parameters apart from a longer PFN incision (P<0.00). First postoperative day pain score was significantly less in the PFN group than in the EPS group (P=0.023). Complication rate was less in the PFN group, although not statistically significant. Hospital stay was significantly shorter in the PFN than in the EPS group (P=0.01). Mean cosmesis and operative satisfaction scores at week 1, week 6, and 6 month visits were not significantly different between both groups. Compared with the EPS group, PFN group patients significantly will choose the same operation if they would do it again (P=0.004). CONCLUSIONS PFN incision has less morbidity, pain score, and hospital stay compared with EPS incision for intact specimen extraction after transperitoneal laparoscopic radical nephrectomy. Both incisions are associated with high operative satisfaction, good cosmesis, and a low rate of wound complications.
-
6.
Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial.
Motzer, RJ, Hutson, TE, Glen, H, Michaelson, MD, Molina, A, Eisen, T, Jassem, J, Zolnierek, J, Maroto, JP, Mellado, B, et al
The Lancet. Oncology. 2015;(15):1473-1482
Abstract
BACKGROUND Currently, metastatic renal cell carcinoma is treated with sequential single agents targeting VEGF or mTOR. Here, we aimed to assess lenvatinib, everolimus, or their combination as second-line treatment in patients with metastatic renal cell carcinoma. METHODS We did a randomised, phase 2, open-label, multicentre trial at 37 centres in five countries and enrolled patients with advanced or metastatic, clear-cell, renal cell carcinoma. We included patients who had received treatment with a VEGF-targeted therapy and progressed on or within 9 months of stopping that agent. Patients were randomised via an interactive voice response system in a 1:1:1 ratio to either lenvatinib (24 mg/day), everolimus (10 mg/day), or lenvatinib plus everolimus (18 mg/day and 5 mg/day, respectively) administered orally in continuous 28-day cycles until disease progression or unacceptable toxic effects. The randomisation procedure dynamically minimised imbalances between treatment groups for the stratification factors haemoglobin and corrected serum calcium. The primary objective was progression-free survival in the intention-to-treat population. This study is closed to enrolment but patients' treatment and follow-up is ongoing. This study is registered with ClinicalTrials.gov, number NCT01136733. FINDINGS Between March 16, 2012, and June 19, 2013, 153 patients were randomly allocated to receive either the combination of lenvatinib plus everolimus (n=51), single-agent lenvatinib (n=52), or single-agent everolimus (n=50). Lenvatinib plus everolimus significantly prolonged progression-free survival compared with everolimus alone (median 14·6 months [95% CI 5·9-20·1] vs 5·5 months [3·5-7·1]; hazard ratio [HR] 0·40, 95% CI 0·24-0·68; p=0·0005), but not compared with lenvatinib alone (7·4 months [95% CI 5·6-10·2]; HR 0·66, 95% CI 0·30-1·10; p=0·12). Single-agent lenvatinib significantly prolonged progression-free survival compared with everolimus alone (HR 0·61, 95% CI 0·38-0·98; p=0·048). Grade 3 and 4 events occurred in fewer patients allocated single-agent everolimus (25 [50%]) compared with those assigned lenvatinib alone (41 [79%]) or lenvatinib plus everolimus (36 [71%]). The most common grade 3 or 4 treatment-emergent adverse event in patients allocated lenvatinib plus everolimus was diarrhoea (ten [20%]), in those assigned single-agent lenvatinib it was proteinuria (ten [19%]), and in those assigned single-agent everolimus it was anaemia (six [12%]). Two deaths were deemed related to study drug, one cerebral haemorrhage in the lenvatinib plus everolimus group and one myocardial infarction with single-agent lenvatinib. INTERPRETATION Lenvatinib plus everolimus and lenvatinib alone resulted in a progression-free survival benefit for patients with metastatic renal cell carcinoma who have progressed after one previous VEGF-targeted therapy. Further study of lenvatinib is warranted in patients with metastatic renal cell carcinoma. FUNDING Eisai Inc.
-
7.
Hypertension among patients with renal cell carcinoma receiving axitinib or sorafenib: analysis from the randomized phase III AXIS trial.
Rini, BI, Quinn, DI, Baum, M, Wood, LS, Tarazi, J, Rosbrook, B, Arruda, LS, Cisar, L, Roberts, WG, Kim, S, et al
Targeted oncology. 2015;(1):45-53
-
-
Free full text
-
Abstract
Inhibitors of the vascular endothelial growth factor (VEGF) pathway frequently induce hypertension when used to treat patients with advanced renal cell carcinoma (RCC). This analysis characterizes hypertension and hypertension-related events in patients treated with the VEGF pathway inhibitors axitinib or sorafenib in the AXIS trial. AXIS was a randomized phase III study of axitinib versus sorafenib in patients with metastatic RCC following failure of one prior systemic regimen. Patients with uncontrolled hypertension were excluded, but patients with hypertension controlled with antihypertensive medication were allowed to participate. Guidelines for hypertension management included adjustment or addition of antihypertensive medications and/or axitinib or sorafenib dose reductions, interruptions, or discontinuations. Treatment-emergent all-causality hypertension occurred in 145 (40.4 %) axitinib-treated patients (N = 359) and 103 (29.0 %) sorafenib-treated patients (N = 355), with grade 3 hypertension reported in 55 (15.3 %) and 38 (10.7 %) patients, respectively, and grade 4 hypertension reported in one (0.3 %) patient in each arm. Hypertension-related events led to axitinib dose interruptions (n = 46; 12.8 %), dose reductions (n = 16; 4.5 %), or discontinuations (n = 1; 0.3 %). Approximately 50 % of axitinib-treated patients with grade 3 or 4 hypertension continued treatment for ≥ 9 months. Hypertension-related sequelae occurred in <1 % of axitinib-treated patients. Hypertension was more frequently observed during treatment with axitinib than sorafenib in patients with RCC, but axitinib-induced hypertension rarely led to treatment discontinuation or cardiovascular sequelae. Recommendations for monitoring blood pressure and managing hypertension during axitinib therapy are presented.
-
8.
Are tyrosine kinase inhibitors still active in patients with metastatic renal cell carcinoma previously treated with a tyrosine kinase inhibitor and everolimus? Experience of 36 patients treated in France in the RECORD-1 Trial.
Blesius, A, Beuselinck, B, Chevreau, C, Ravaud, A, Rolland, F, Oudard, S, Escudier, B
Clinical genitourinary cancer. 2013;(2):128-33
Abstract
BACKGROUND Because the response to treatment is limited, patients with metastatic renal cell carcinoma (mRCC) typically receive multiple treatments. Guidelines recommend everolimus for patients previously treated with tyrosine kinase inhibitors (TKI) sunitinib or sorafenib. This study evaluated the efficacy of TKI re-treatment in patients with disease progression after a TKI-everolimus sequence. PATIENTS AND METHODS Data were reviewed for patients enrolled in RECORD-1 (Renal Cell Cancer Treatment With Oral RAD001 Given Daily) at French sites. Response, progression-free survival (PFS), and overall survival were evaluated in patients treated with a TKI-everolimus-TKI sequence. RESULTS Thirty-six patients received a TKI after everolimus: sunitinib in 17 patients, sorafenib in 15, and dovitinib (TKI258) in 4. The response rate with TKI re-treatment was 8%, and the disease-control rate (response plus stable disease) was 75%. The median PFS with each component of the TKI-everolimus-TKI sequence was 10.7 months (95% CI, 1.8-28.5 months), 8.9 months (95% CI, 1.7-34.6 months), and 8.2 months (95% CI, 5.2-11.9 months), respectively. The median overall survival from the start of everolimus was 29.1 months (95% CI 21.1 to not reached months), which suggests a benefit in using TKI in this setting. CONCLUSIONS Administration of a TKI-everolimus-TKI sequence may be associated with clinical benefit and should be prospectively investigated.
-
9.
Patient-reported outcomes for axitinib vs sorafenib in metastatic renal cell carcinoma: phase III (AXIS) trial.
Cella, D, Escudier, B, Rini, B, Chen, C, Bhattacharyya, H, Tarazi, J, Rosbrook, B, Kim, S, Motzer, R
British journal of cancer. 2013;(8):1571-8
-
-
Free full text
-
Abstract
BACKGROUND Axitinib demonstrated greater progression-free survival vs sorafenib in a phase III study of previously treated patients with metastatic renal cell carcinoma. Here, we report patient-reported kidney-specific symptoms and health status, measured by the Functional Assessment of Cancer Therapy (FACT) Kidney Cancer Symptom Index (FKSI) and the European Quality of Life self-report questionnaire (EQ-5D). METHODS In all, 723 patients received axitinib (starting dose 5 mg twice daily (b.i.d.)) or sorafenib (400 mg b.i.d.). The FKSI-15, including the disease-related symptoms (FKSI-DRS) subscale, was administered on day 1 before dosing, every 4 weeks and at end of treatment (EOT)/withdrawal. Statistical methods included a mixed-effects repeated-measures model. RESULTS At baseline, patients in both arms had relatively high mean FSKI-15 and FKSI-DRS scores, comparable to the general US population. Subsequent on-treatment overall mean scores were similar between axitinib and sorafenib, and there was no substantial decline during treatment. Scores substantially worsened at EOT, mainly due to disease progression. CONCLUSION Patient-reported outcomes were comparable for second-line axitinib and sorafenib and were maintained at relatively high levels while on treatment, but worsened at EOT. As duration of treatment was longer with axitinib than sorafenib, time to worsening of symptoms can be delayed longer with axitinib.
-
10.
Effect of remote ischaemic preconditioning on renal protection in patients undergoing laparoscopic partial nephrectomy: a 'blinded' randomised controlled trial.
Huang, J, Chen, Y, Dong, B, Kong, W, Zhang, J, Xue, W, Liu, D, Huang, Y
BJU international. 2013;(1):74-80
Abstract
OBJECTIVE To evaluate whether remote ischaemic preconditioning (RIPC) reduces renal injury in patients undergoing laparoscopic partial nephrectomy (LPN). PATIENTS AND METHODS In all, 82 patients undergoing LPN were randomly assigned to either the RIPC or control group, with 40 and 38 patients, respectively completing 6-months follow-up. RIPC was conducted after induction of anaesthesia, which consisted of three 5-min cycles of right lower limb ischaemia and 5 min of reperfusion during each cycle. The primary outcome was the absolute change in glomerular filtration rate (GFR) of the affected kidney by renal scintigraphy from baseline to 6 months. The secondary outcomes included urinary retinol-binding protein (RBP) levels measured at 24 and 48 h, serum creatinine, and estimated GFR (eGFR) at 1 and 6 months, and changes in GFR by renal scintigraphy. RESULTS There were no differences in the change of GFR of the affected kidney at 6 months, while it was significantly decreased by 15.0% in the control group vs 8.8% in the RIPC group at 1 month (P = 0.034). The urinary RBP levels increased 8.4-fold at 24 h in the control group compared with a lower increase of 3.9-fold in the RIPC group (P < 0.001). There were no differences in the serum creatinine level or eGFR at 1 and 6 months between the two groups. CONCLUSIONS In patients undergoing LPN, RIPC using transient lower limb ischaemia may reduce renal impairment in the short term, but failed in the longer term despite a non-significant trend in favour of RIPC. These novel data support the need for a larger study of RIPC during LPN surgery.