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Objectives: The recent approval of first-line tyrosine kinase inhibitor plus immuno-oncology agent combination therapy for the treatment of advanced renal cell carcinoma offers substantially improved response rates and survival compared with the previous standard of care. This expansion of treatment options has also led to a greater range and complexity of potential treatment-related adverse events related to overlapping toxicities. The aim of this article is to discuss the management of common treatment-emergent adverse events (AEs) associated with axitinib plus immuno-oncology therapy, highlight the specific roles of oncology nurses in managing these events, and provide AE management resources to aid oncology nurses in their care of patients with advanced renal cell carcinoma., Data Sources: Author experience, journal articles, and treatment guidelines were used., Conclusion: The use of oncology nurses and nurse-led innovations to monitor and assess treatments can have a positive impact on the management of AEs in cancer patients by identifying those who are most at risk, providing regular assessment, appropriate patient education, and supporting the monitoring of patient safety., Implications for Nursing Practice: Skilled oncology nurses should be a key part of a team that addresses the supportive care needs and management of AEs that are associated with novel cancer treatments. Early and ongoing communication between the patient and oncology nurses regarding the development of adverse events is a critical component of maximizing treatment outcomes and quality of life., Competing Interests: Declaration of competing interest Sara Parreira, Kathleen Burns, Nancy Moldawer, Nazy Zomordian, Nesan Bandali, Kiran Virdee, Meghara Walsh and Laura Wood have no disclosures to report. Daniel Kelly is a member of a team of Grant Recipients from Pfizer to conduct an independent medical education program entitled “RCC4Nurses: Improving quality of nursing care in metastatic renal cell carcinoma” with the University of Glasgow and the European Oncology Nursing Society. Dharanija Rao and Rosemary Teresi are full-time employees and hold stock or stock options in Pfizer., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Ipilimumab plus nivolumab has been approved for intermediate- and poor-risk metastatic renal cell carcinoma (RCC). However, the activity in non-clear cell RCC (nccRCC) is unknown., Patients and Methods: Patients from Cleveland Clinic and the University of Texas Southwestern who had received ipilimumab plus nivolumab for metastatic nccRCC from October 2017 to May 2019 were retrospectively identified. Ipilimumab plus nivolumab was administered in accordance with the CHECKMATE 214 trial. Imaging was obtained at baseline and every 12 weeks. The baseline patient characteristics, objective response per Response Evaluation Criteria in Solid Tumors, version 1.1, and treatment-related adverse events (TRAEs) per Common Terminology Criteria for Adverse Events, version 5.0, were analyzed., Results: Eighteen patients were identified. The median age was 59 years (range, 32-81 years), 77.8% were men, and the Eastern Cooperative Oncology Group performance status was 0 (38%) or 1 (50%). The median treatment duration was 2.4 months (range, 0.7-12.3 months). The non-clear cell histologic types included 6 papillary, 5 chromophobe, 3 unclassified, 2 adenocarcinoma of renal origin, 1 translocation, and 1 medullary. Most had an intermediate (66%) or poor (22%) International Metastatic Database Consortium risk. The best objective response included 6 partial responses (PRs; 33.3%) and 3 with stable disease (16.7%). Of the patients with a PR, the median time to the best response was 3.0 months, and median duration of the PR was 4.3 months. The median progression-free survival was 7.1 months. All-grade TRAEs were noted in 11 patients (61.1%) and included colitis (22%), hepatotoxicity (16%), rash (11%), and fatigue (11%). Eleven patients (61%) had TRAEs requiring high-dose glucocorticoids (> 40 mg of prednisone equivalent daily)., Conclusions: Ipilimumab plus nivolumab demonstrated objective responses and notable toxicity in patients with nccRCC., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Immune checkpoint inhibitors have improved clinical outcomes in many malignancies, including renal cell carcinoma (RCC). Awareness of potential adverse events and effective management of these toxicities is critical to maximizing clinical outcomes. Pembrolizumab plus axitinib is approved as front-line treatment of advanced renal cell carcinoma (aRCC), making it the first checkpoint inhibitor and tyrosine kinase inhibitor combination approved for any malignancy. Given overlapping toxicities with this combination, the toxicity profile of each drug must be considered when assessing and managing toxicities in patients treated with pembrolizumab and axitinib. Use of online resources, including published guidelines from ASCO, the Immuno-Oncology Essentials Web site, and other organizations, can assist oncology and nononcology health care professionals to more effectively manage toxicities, maximize clinical outcomes, and improve quality of life for patients with aRCC. Herein, we describe a case of a patient with aRCC treated with pembrolizumab and axitinib, highlighting a systematic approach to toxicity management.

The approval of immunotherapeutic agents and immunotherapy-based combination strategies in recent years has revolutionized the treatment of patients with advanced renal cell carcinoma (aRCC). Nivolumab, a programmed death 1 (PD-1) immune checkpoint inhibitor monoclonal antibody, was approved as monotherapy in 2015 for aRCC after treatment with a VEGF-targeting agent. In April 2018, the combination of nivolumab and ipilimumab, a CTLA-4 inhibitor, was approved for intermediate- and poor-risk, previously untreated patients with aRCC. Then, in 2019, combinations therapies consisting of pembrolizumab (anti-PD-1) or avelumab (anti-PD-ligand (L) 1) with axitinib (a VEGF receptor tyrosine kinase inhibitor) were also approved to treat aRCC and are likely to produce dramatic shifts in the therapeutic landscape. To address the rapid advances in immunotherapy options for patients with aRCC, the Society for Immunotherapy of Cancer (SITC) reconvened its Cancer Immunotherapy Guidelines (CIG) Renal Cell Carcinoma Subcommittee and tasked it with generating updated consensus recommendations for the treatment of patients with this disease.

Background: Checkpoint inhibitor therapy is a standard of care for patients with metastatic renal cell carcinoma. Treatment options after checkpoint inhibitor therapy include vascular endothelial growth factor receptor (VEGF-R) tyrosine kinase inhibitors, although no prospective data regarding their use in this setting exist. Axitinib is a VEGF-R inhibitor with clinical data supporting increased activity with dose titration. We aimed to investigate the activity of dose titrated axitinib in patients with metastatic renal cell carcinoma who were previously treated with checkpoint inhibitor., Methods: We did a multicentre, phase 2 trial of axitinib given on an individualised dosing algorithm. Patients at least 18 years of age with histologically or cytologically confirmed locally recurrent or metastatic renal cell carcinoma with clear cell histology, a Karnofsky Performance Status of 70% or more, and measurable disease who received checkpoint inhibitor therapy as the most recent treatment were eligible. There was no limit on number of previous therapies received. Patients received oral axitinib at a starting dose of 5 mg twice daily with dose titration every 14 days in 1 mg increments (ie, 5 mg twice daily to 6 mg twice daily, up to 10 mg twice daily maximum dose) if there was no axitinib-related grade 2 or higher mucositis, diarrhoea, hand-foot syndrome, or fatigue. If one or more of these grade 2 adverse events occurred, axitinib was withheld for 3 days before the same dose was resumed. Dose reductions were made if recurrent grade 2 adverse events despite treatment breaks or grade 3-4 adverse events occurred. The primary outcome was progression-free survival. Analyses were done per protocol in all patients who received at least one dose of axitinib. Recruitment has been completed and the trial is ongoing. This trial is registered with ClincalTrials.gov, number NCT02579811., Findings: Between Jan 5, 2016 and Feb 21, 2018, 40 patients were enrolled and received at least one dose of study treatment. With a median follow-up of 8·7 months (IQR 3·7-14·2), the median progression-free survival was 8·8 months (95% CI 5·7-16·6). Fatigue (83%) and hypertension (75%) were the most common all-grade adverse events. The most common grade 3 adverse event was hypertension (24 patients [60%]). There was one (3%) grade 4 adverse event (elevated lipase) and no treatment-related deaths occurred. Serious adverse events that were likely related to therapy occurred in eight (20%) patients; the most common were dehydration (n=4) and diarrhoea (n=2)., Interpretation: Individualised axitinib dosing in patients with metastatic renal cell inoma previously treated with checkpoint inhibitors did not meet the prespecified threshold for progression free survival, but these data show that this individualised titration scheme is feasible and has robust clinical activity. These prospective results warrant consideration of axitinib in this setting., Funding: Pfizer., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Nivolumab is approved for mRCC patients who have received prior anti-angiogenic therapy but the duration of therapy required for sustained clinical benefit is unknown. A phase II clinical trial to investigate the feasibility of intermittent nivolumab dosing was conducted., Methods: Patients ≥18 years of age with mRCC who were previously treated with at least one antiangiogenic therapy were eligible. Patients were treated with nivolumab for twelve weeks. Patients who had RECIST PD were removed from the trial. Patients who did not initially achieve ≥10% reduction in tumor burden (TB) continued nivolumab per standard of care. Patients with ≥10% TB reduction entered a treatment-free observation phase with re-imaging every 12 weeks. Nivolumab was restarted in patients with a ≥ 10% TB increase and again held with TB reduction ≥10%. This intermittent nivolumab dosing continued until RECIST PD while on nivolumab. The primary objective was feasibility of intermittent nivolumab, defined as the proportion of patients eligible for intermittent therapy who elect to receive intermittent nivolumab. Intermittent nivolumab would be considered "feasible" if the acceptance rate was ≥80%. Forty patients provides > 95% power with 0.05 type I error, assuming a null acceptance rate of 50%. With the approval of the combination of ipilimumab/nivolumab (April 2018) in front-line mRCC, this cohort was closed prior to completed pre-planned approval., Results: Of the 14 patients enrolled, 13 (93%) were male with a median age 65. All had a prior nephrectomy and 12 (86%) were intermediate-risk by IMDC criteria. Five patients (36%) met the criteria for the intermittent phase of the trial (median TB decrease 46%) and all agreed to intermittent therapy. With a median follow-up of 48 weeks, only one patient restarted therapy. The four remaining patients have a sustained response for a median of 34 weeks (range, 16-53) off therapy. No patients developed RECIST PD while off therapy., Conclusions: This prospective experience of intermittent nivolumab dosing in mRCC supports further investigation of intermittent immunotherapy dosing strategies in RCC., Trial Registration: NCT03126331 (Intermittent Nivolumab in Metastatic Renal Cell Carcinoma Patients; Date of registration 4/27/2017; https://clinicaltrials.gov/ct2/show/NCT03126331 ).

Background: Nivolumab is approved for the treatment of refractory metastatic renal cell carcinoma. Patterns and predictors of progressive disease (PD) on nivolumab, and outcomes in such patients are lacking., Methods: A retrospective analysis of patients (pts) with metastatic clear cell renal cell carcinoma (ccRCC) who received nivolumab at Cleveland Clinic (2015-2017) was performed. PD was defined per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 or clinical progression as per treating physician. Univariate analyses (UVA) and multivariate analyses (MVA) were used to identify clinical and laboratory markers as potential predictors of progression-free survival (PFS)., Results: Ninety patients with mean age of 65, 74% men, and 83% good or intermediate International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk group were included. Median number of prior systemic treatments was 2 (range, 1-6). Median overall survival (OS) and PFS were 15.8 and 4.4 months, respectively. Fifty-seven patients (63%) had PD and 44% of patients with radiographic PD had new organ sites of metastases with brain (8/23, 35%) being the most common. Twelve patients received treatment beyond progression (TBP), and among 6 patients with available data, 3 (50%) had any tumor shrinkage (2 pts. with 17% shrinkage, one pt. with 29% shrinkage). Of 57 patients with PD, 28 patients (49%) were able to initiate subsequent treatment, mainly with axitinib and cabozantinib, while 40% of patients were transitioned to hospice after PD. In MVA, a higher baseline Neutrophil-to-Lymphocyte ratio (NLR) (HR, 1.86; 95% CI, 1.05-3.29; p = 0.033) was associated with an increased risk of progression, whereas higher (> 0.1 k/uL) baseline eosinophil count was associated with a lower risk of progression (HR, 0.54; 95% CI, 0.30-0.98; p = 0.042)., Conclusion: Brain was the most common site of PD in patients treated with nivolumab, and only half of patients progressing on nivolumab were able to initiate subsequent treatment. The risk of PD increased with a higher baseline NLR and reduced with a higher baseline eosinophil count.

Background: We assessed the clinical outcomes of patients with oligoprogressive renal cell carcinoma (mRCC) treated with stereotactic radiosurgery (SRS), stratified by changing or continuing systemic treatment., Patients and Methods: Ninety-five consecutive patients with clear cell mRCC who had undergone SRS to the central nervous system (CNS) or spine during systemic treatment were divided into 3 cohorts: those who continued the same systemic therapy (STAY), those who changed systemic treatment after SRS (SWITCH), and patients with progression outside the SRS sites, who also changed systemic treatment (PD-SYS). The primary outcome was treatment duration after SRS, defined as the interval between SRS and discontinuation of the current systemic therapy for the STAY group and discontinuation of the first subsequent therapy in the SWITCH and PD-SYS groups., Results: Local control with SRS was achieved in 85% of the patients. The most common systemic treatment at SRS included anti-vascular endothelial growth factor (67%), mammalian target of rapamycin (14%), and programmed cell death protein 1 inhibitors (9%). The median treatment duration for the STAY group was 5.2 months (95% confidence interval [CI], 3.5-6.9) compared with 5.0 months (95% CI, 4.3-5.7) for the SWITCH group (P = .549) and 3.1 months (95% CI, 1.7-4.5) for the PD-SYS group (P = .07, compared with all other patients). No difference in median overall survival was found for the STAY and SWITCH groups (24.2 vs. 27.1 months; P = .381) but was significantly longer than that for the PD-SYS group (P = .025)., Conclusion: The decision to continue the same systemic therapy at SRS to treat CNS or spinal lesions did not compromise the clinical outcomes of patients with oligoprogressive mRCC., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Improved overall survival of cancer patients treated by high-volume providers has been reported in surgical oncology and radiation oncology literature. Whether this volume-outcome association exists in medical oncology-managed metastatic solid tumors is uncertain. This study aimed to investigate the effect of facility case volume (FCV) on overall survival in patients with metastatic renal cell carcinoma (mRCC) diagnosed in the targeted therapy era., Materials and Methods: Adult patients diagnosed with mRCC between 2006 and 2015 were identified in the National Cancer Database. The primary exposure was FCV, which was defined by mRCC case volume of each treating facility. The association between FCV and all-cause mortality in mRCC was investigated in multivariable Cox regression model and validated with inverse propensity-score weighting method. Logistic regression was used to identify independent predictors for treatment at high-volume facilities. Covariates adjusted for were sociodemographics, tumor characteristics and treatment modalities., Results: There were 31,329 mRCC patients identified. The mean follow-up time was 14.3 months. When FCV was coded as a continuous variable, each increment of 10 mRCC cases/y was associated with reduced all-cause mortality after baseline covariates adjustment [adjusted hazard ratio: 0.93, 95% confidence interval: 0.90-0.96, P value:<0.0001]. In dichotomized models, improved all-cause mortality was observed at cutoffs of 85th (4.3 cases/y), 90th (5.4 cases/y) and 95th (7.4 cases/y) but not at 50th (2.2 cases/y) and 75th (3.4 cases/y) percentiles. For illustrative purpose, 95th percentile was chosen and inverse propensity-score weighting-adjusted Kaplan-Meier curve demonstrated improved overall survival for mRCC patients treated at high-volume facilities (adjusted hazard ratio: 0.90, 95% confidence interval: 0.88-0.94, P value <0.0001; the 1-, 2-, 3-year survival rates were 41%, 26%, and 19% vs. 36%, 22%, and 16% for patients treated at high and low-volume facilities, respectively). Patients without insurance or with Medicaid status, with shorter travel distance, living in nonmetropolitan area or in area with lower averaged education level were less likely to be treated at high-volume facilities., Conclusions: Patients diagnosed with mRCC in the targeted therapy era have improved overall survival when treated at high mRCC-volume facilities, suggesting a volume-outcome association in medical oncology-managed metastatic solid tumors., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: The outcome of patients who progress on front-line immune-based combination regimens (IC) including immune checkpoint inhibitors (CPI) and receive subsequent systemic therapy is unknown., Methods: Retrospective analysis of consecutive patients with clear-cell mRCC who progressed on one of seven clinical trials investigating an IC and received ≥1 line of subsequent VEGFR TKI therapy., Results: Thirty-three patients [median age 57 (37-77), 85% male, 73% ECOG 0] were included. For evaluable patients (N = 28), the best response to first subsequent therapy was 29% partial response, 54% stable disease, and 18% progressive disease. The median PFS (mPFS) for first subsequent therapy was 6.4 months (95% CI, 4.4-8.4); no difference in mPFS by prior type of IC (VEGFR TKI-CPI vs. CPI-CPI) was noted (p = 0.310). Significant AEs were observed in 30% of patients, more frequently transaminitis (9%)., Conclusions: VEGFR TKIs have clinical activity in mRCC refractory to IC therapy, possibly impacted by the mechanism of prior combination therapy.

Introduction: Tyrosine kinase inhibitor (TKI) therapy in metastatic renal-cell carcinoma (mRCC) is noncurative and may be associated with significant toxicities. Some patients may receive treatment breaks as a result of TKI-related adverse effects or planned drug holidays., Patients and Methods: In this retrospective study, mRCC patients who underwent drug holidays during TKI therapy at 2 different institutions were analyzed. A drug holiday was defined as a period of drug cessation for ≥ 3 months for reasons other than progressive disease., Results: Of the 112 patients, the median duration of the first drug holiday for the overall cohort was 16.8 months (95% confidence interval, 12.5-26.4), and 40 patients (36%) remain on the first drug holiday. Overall, patients received a median of 2 lines of treatment. Complete response before the initial drug holiday (n = 14) was associated with a longer surveillance period (P = .0004). The observed median survival of this cohort was 71.7 months (range, 1.3 to 93+ months)., Conclusion: Some selected mRCC patients with a favorable response to TKIs may be eligible for drug holidays. The cohort evaluated in this retrospective study represents a highly selected group of patients with indolent disease biology., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose Sunitinib is a standard initial therapy in metastatic renal cell carcinoma (mRCC), but chronic dosing requires balancing toxicity with clinical benefit. The feasibility and clinical outcome with intermittent sunitinib dosing in patients with mRCC was explored. Patients and Methods Patients with treatment-naïve, clear cell mRCC were treated with four cycles of sunitinib (50 mg once per day, 4 weeks of receiving treatment followed by 2 weeks of no treatment). Patients with a ≥ 10% reduction in tumor burden (TB) after four cycles had sunitinib held, with restaging scans performed every two cycles. Sunitinib was reinitiated for two cycles in those patients with an increase in TB by ≥ 10%, and again held with ≥ 10% TB reduction. This intermittent sunitinib dosing continued until Response Evaluation Criteria in Solid Tumors-defined disease progression while receiving sunitinib, or unacceptable toxicity occurred. The primary objective was feasibility, defined as the proportion of eligible patients who underwent intermittent therapy. Results Of 37 patients enrolled, 20 were eligible for intermittent therapy and all patients (100%) entered the intermittent phase. Patients were not eligible for intermittent sunitinib because of progressive disease (n = 13), toxicity (n = 1), or consent withdrawal (n = 3) before the end of cycle 4. The objective response rate was 46% after the first four cycles of therapy. The median increase in TB during the periods off sunitinib was 1.6 cm (range, -2.9 to 3.4 cm) compared with the TB immediately before stopping sunitinib. Most patients exhibited a stable sawtooth pattern of TB reduction while receiving sunitinib and TB increase while not receiving sunitinib. Median progression-free survival to date is 22.4 months (95% CI, 5.4 to 37.6 months) and median overall survival is 34.8 months (95% CI, 14.8 months to not applicable). Conclusion Periodic extended sunitinib treatment breaks are feasible and clinical efficacy does not seem to be compromised.

Background: Given the variability in drug levels with tyrosine kinase inhibitors (TKIs) in patients with metastatic renal cell carcinoma (mRCC), dose escalation at the occurrence of progressive disease (PD) might have antitumor effects., Patients and Methods: The data from patients with mRCC who were treated at the Cleveland Clinic with TKIs and received a dose escalation after PD in accordance with Response Evaluation Criteria In Solid Tumors (RECIST), version 1.1, were retrospectively reviewed. Patient- and disease-related data were collected and summarized as frequency counts and percentages or medians and ranges. The Kaplan-Meier method was used to summarize the treatment duration for the escalated doses., Results: Twenty-two patients were identified. Most patients (82%) were men; the median age at diagnosis was 58 years (range, 40-71 years). The most common histologic type was clear cell (73%). Axitinib was the most frequently escalated agent after PD (17 patients), followed by sunitinib (3 patients), and pazopanib (2 patients). Before PD, the median treatment duration was 6.8 months (range, 1.6-50.6 months). Of the 18 patients with evaluable tumor measurements after dose escalation, 14 (78%) had a decrease in tumor burden. The median decrease in tumor burden after dose escalation was 14% (range, 2%-58%); 4 patients (22%) had decreases ≥10%, 2 (11%) ≥20%, and 4 (22%) >30% (RECIST partial response). At the last follow-up examination, 5 patients (23%) continued to be treated at escalated doses. The median duration of escalated therapy was estimated at 10.1 months (range, 0.6 to 37.9 months)., Conclusion: Dose escalation of TKIs after PD for select patients with mRCC can lead to a reduction in tumor burden and extend the duration of therapy., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Immunotherapy has produced durable clinical benefit in patients with metastatic renal cell cancer (RCC). In the past, patients treated with interferon-alpha (IFN) and interleukin-2 (IL-2) have achieved complete responses, many of which have lasted for multiple decades. More recently, a large number of new agents have been approved for RCC, several of which attack tumor angiogenesis by inhibiting vascular endothelial growth factors (VEGF) and VEGF receptors (VEGFR), as well as tumor metabolism, inhibiting the mammalian target of rapamycin (mTOR). Additionally, a new class of immunotherapy agents, immune checkpoint inhibitors, is emerging and will play a significant role in the treatment of patients with RCC. Therefore, the Society for Immunotherapy of Cancer (SITC) convened a Task Force, which met to consider the current role of approved immunotherapy agents in RCC, to provide guidance to practicing clinicians by developing consensus recommendations and to set the stage for future immunotherapeutic developments in RCC.

Background: A subset of patients with metastatic renal-cell carcinoma show indolent growth of metastases. Because of the toxicity and non-curative nature of systemic therapy, some of these patients could benefit from initial active surveillance. We aimed to characterise the time to initiation of systemic therapy in patients with metastatic renal-cell carcinoma under active surveillance., Methods: In this prospective phase 2 trial, we enrolled patients with treatment-naive, asymptomatic, metastatic renal-cell carcinoma from five hospitals in the USA, Spain, and the UK. Patients were radiographically assessed at baseline, every 3 months for year 1, every 4 months for year 2, then every 6 months thereafter. Patients continued on observation until initiation of systemic therapy for metastatic renal-cell carcinoma; a decision that was made at the discretion of the treating physician and patient. The primary endpoint of the study was time to initiation of systemic therapy in the per-protocol population. The follow-up of patients is ongoing., Findings: Between Aug 21, 2008, and June 7, 2013, we enrolled 52 patients. Median follow-up of patients in the study was 38·1 months (IQR 29·4-48·9). In the 48 patients included in analysis, median time on surveillance from registration on study until initiation of systemic therapy was 14·9 months (95% CI 10·6-25·0). Multivariate analysis showed that higher numbers of International Metastatic Database Consortium (IMDC) adverse risk factors (p=0·0403) and higher numbers of metastatic disease sites (p=0·0414) were associated with a shorter surveillance period. 22 (46%) patients died during the study period, all from metastatic renal-cell carcinoma., Interpretation: A subset of patients with metastatic renal-cell carcinoma can safely undergo surveillance before starting systemic therapy. Additional investigation is required to further define the benefits and risks of this approach., Funding: None., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Axitinib is a potent inhibitor of the vascular endothelial growth factor (VEGF) receptor family with clinical activity in patients with metastatic renal cell carcinoma (mRCC). Given this biochemical potency, the clinical activity of subsequent treatment with targeted therapies in patients progressing on axitinib is of interest., Methods: Patients with advanced renal cell carcinoma of any pathologic subtype treated with at least one cycle (four weeks) of axitinib followed by at least one subsequent targeted therapy were investigated in a retrospective analysis. Patient characteristics, duration of treatment and clinical outcomes were analyzed for axitinib and each subsequent line of therapy by Response Evaluation Criteria in Solid Tumors (RECIST)., Results: Twenty-five mRCC patients who received at least one approved targeted agent following axitinib were identified. Eight percent of patients achieved a partial response (one patient each to sunitinib and pazopanib) and 42 % had a best response of stable disease to the first therapy after axitinib. The estimated median duration of therapy was 4.4 months (range, 0.2-27.5+). Twelve patients received a second post-axitinib targeted therapy. Six out of 11 evaluable patients (55 %) had a best response of SD. The estimated median duration of treatment was 4.8 months (range, 0.7-19.1+)., Conclusion: Objective responses and stable disease is observed to post-axitinib targeted therapies and prospective studies are needed for validating role of predictive biomarkers.

Purpose: Preservation of renal function is prioritized during surgical management of localized renal cell carcinoma. VEGF targeted agents can downsize tumors in metastatic renal cell carcinoma and may do the same in localized renal cell carcinoma, allowing for optimal preservation of renal parenchyma associated with partial nephrectomy., Materials and Methods: Localized clear cell renal cell carcinoma patients meeting 1 or both of the following criteria were enrolled in a prospective phase II trial, including radical or partial nephrectomy likely to yield a glomerular filtration rate of less than 30 ml/minute/1.73 m(2), or partial nephrectomy high risk due to high complexity (R.E.N.A.L. 10 to 12) or tumor adjacent to hilar vessels. Pazopanib (800 mg once daily) was administered for 8 to 16 weeks with repeat imaging at completion of therapy, followed by surgery., Results: A total of 25 patients enrolled with a median tumor size of 7.3 cm and a median R.E.N.A.L. score of 11. Of index lesions 80% were high complexity and 56% of patients had a solitary kidney. Patients received a median of 8 weeks of pazopanib. The median interval from treatment start to surgery was 10.6 weeks. R.E.N.A.L. score decreased in 71% of tumors and 92% of patients experienced a reduction in tumor volume. Six of 13 patients for whom partial nephrectomy was not possible at baseline were able to undergo partial nephrectomy after treatment. The mean parenchymal volume that could be saved with surgery increased from an estimated 107 to 173 cc (p = 0.0015). In 5 patients a urine leak developed, which was managed conservatively, and 7 received a transfusion, of whom 1 required embolization., Conclusions: Neoadjuvant pazopanib resulted in downsizing localized renal cell carcinoma, allowing for improved preservation of renal parenchyma and enabling partial nephrectomy 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.)

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.

Axitinib is a novel, oral, multitargeted tyrosine kinase inhibitor, which inhibits vascular endothelial growth factor receptors 1, 2, and 3 at subnanomolar concentrations in vitro. In the phase III clinical trial in patients with metastatic renal cell carcinoma, axitinib showed a high objective response rate, and significantly prolonged progression-free survival compared with sorafenib. Thus, it is the first drug that has proven the concept of sequencing tyrosine kinase inhibitors in second-line treatment in a phase III prospective randomized trial. Although generally well tolerated and associated with a low incidence of grade 3 or 4 toxicities, axitinib shows a distinct pattern of adverse events that require monitoring and management. The most common adverse events observed with axitinib include diarrhea, hypertension, fatigue, nausea, and vomiting. This article summarizes the most important adverse events observed and proposes recommendations for their monitoring, prevention, and treatment. The recommendations are based on the existing literature and discussion by an expert group of international physicians and nurses specialized in oncologic treatment of metastatic renal cell carcinoma, which gathered in July 2011 in London, UK. Proactive assessment and management of adverse events during axitinib therapy can minimize treatment interruptions and ensure optimal effect of treatment.

Background: Multitargeted tyrosine kinase inhibitors (TKIs) have antitumor activity in metastatic renal cell carcinoma (mRCC). Resistance to these agents develops frequently, and their use is often limited by intolerance. Ramucirumab is a recombinant human monoclonal antibody directed against human vascular endothelial growth factor receptor-2. For this study, the authors investigated the clinical efficacy and safety of ramucirumab in patients with TKI-resistant/intolerant mRCC., Methods: In this single-arm phase 2 trial, patients received ramucirumab 8 mg/kg every 2 weeks until they developed disease progression or intolerable toxicity. The primary endpoint was the best objective response rate (ORR); additional endpoints included the disease control rate (DCR), progression-free survival (PFS), the median duration of overall response, and safety., Results: Thirty-nine patients with RCC received ramucirumab monotherapy. Prior TKI therapy included sunitinib (59% of patients), sunitinib and sorafenib (30.8% of patients), and sorafenib (10.3% of patients). The ORR was 5.1% (95% confidence interval [CI], 0.6%-17.3%). The 12-week DCR was 64.1% (95% CI, 47.2%-78.8%). The median PFS was 7.1 months (95% CI, 4.1-9.7 months), and the median overall survival was 24.8 months (95% CI, 18.9-32.6 months). Grade 3 or higher adverse events that occurred in ≥5% of patients included grade 3 hypertension (7.7%) and proteinuria (5.1%). There was 1 on-study death from multiorgan failure., Conclusions: Although the study did not meet its primary endpoint of ≥15% ORR, ramucirumab was associated with evidence of antitumor activity in patients with TKI-resistant/intolerant mRCC. Ramucirumab was safe and well tolerated., (© 2014 American Cancer Society.)

Unlabelled: Neoadjuvant sunitinib might downsize unresectable renal cell carcinoma (RCC) and enable nephrectomy in a subset of patients. After neoadjuvant sunitinib in 27 RCC patients, tumors were resected in 13 patients. Higher attenuation using computed tomography (CT) scans and favorable response according to Morphology, Attenuation, Size, and Structure (MASS) criteria after 2 cycles of sunitinib were independent predictors of subsequent tumor resection., Introduction: In patients with locally advanced and metastatic RCC, selection criteria for nephrectomy are imprecise. Neoadjuvant sunitinib might downsize unresectable tumors and enable nephrectomy. CT scans of unresectable primary RCCs before and after neoadjuvant sunitinib were retrospectively reviewed to identify radiographic features associated with patient selection for surgery., Patients and Methods: CT scans of 27 patients with RCC (31 tumors) treated with neoadjuvant sunitinib were performed as part of a prospective clinical trial. After neoadjuvant sunitinib, tumors were surgically resected in 13 patients (17 tumors) and not resected in 14 patients (14 tumors). Response to treatment with sunitinib was assessed with Response Evaluation Criteria in Solid Tumors and MASS criteria., Results: On the contrast-enhanced CT scan before nephrectomy compared with the baseline CT scan, 88% of resected tumors demonstrated decreased size (median decrease 26%; -2.0 cm; P < .001), 88% had decreased attenuation (median decrease 30%; -27 Hounsfield units; P = .004), and 76% had increased necrosis (P < .001). Response to sunitinib was significantly more favorable (according to MASS criteria) in resected than in nonresected tumors (P = .005). In addition, the degree of baseline necrosis was less in tumors subsequently resected than in nonresected tumors (P = .05). Multivariate analysis showed that higher tumor attenuation after 2 cycles of sunitinib therapy and a favorable response (MASS criteria) after 2 cycles of sunitinib therapy were independent predictors of subsequent tumor resection., Conclusion: In unresectable primary RCC tumors, changes in select CT parameters after 2 cycles of neoadjuvant sunitinib might be associated with the potential for surgical resection., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: The current treatment of metastatic renal cell carcinoma (mRCC) with vascular endothelial growth factor (VEGF)-targeted agents is continuous therapy until progression of disease (PD) or unacceptable toxicity. Chronic mild to moderate toxicity and risk of long-term toxicity ensue for some patients. It is hypothesized that patients with an initial response to treatment can maintain disease control off all therapy for a period of time., Methods: A retrospective study of patients with mRCC who initiated VEGF-targeted therapy between January 2004 and December 2009 at The Cleveland Clinic Foundation, Cleveland, Ohio, or Institut Gustave-Roussy, Villejuif, France, was conducted. Patients had achieved RECIST (Response Evaluation Criteria in Solid Tumors)-defined stable disease or better on therapy, and were then taken off all therapy for reasons not including disease progression. Patient, disease, and therapy characteristics were recorded. The primary objective was progression-free survival (PFS), measured as the time from discontinuation of therapy to RECIST-defined PD., Results: Forty patients were identified. After a median follow-up of 29.7 months (range, 4.2 to 84.7 months), 25 patients (63%) had PD off therapy (median PFS, 10.0 months; range, 1.4-27.2 months). Among these patients, 8 (32%) had progression in sites that were not previously involved with disease. Heng risk group (hazard ratio, 2.49; 95% confidence interval, 1.19-5.22; P = .011) and achievement of a complete response prior to discontinuing therapy (hazard ratio, 0.20; 95% confidence interval, 0.04-0.86; P = .025) were independent predictors of PFS in a multivariable Cox proportional hazards model., Conclusions: A select subset of mRCC patients achieving stable disease or better on VEGF-targeted therapy can be observed off all therapy. Further prospective investigation is warranted., (Copyright © 2011 American Cancer Society.)

Purpose: We investigated the effect of sunitinib on locally advanced primary renal carcinoma tumors and the ability to facilitate subsequent surgery., Materials and Methods: 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., Results: 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., Conclusions: 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., (Copyright © 2012 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Objective: To determine, in a phase I/II trial, the maximum tolerated dose (MTD), clinical activity and safety of concurrent subcutaneous (s.c.) interleukin-2 (IL-2), interferon-α2b (IFN-α) and granulocyte-macrophage colony-stimulating factor (GM-CSF)., Patients and Methods: Patients with metastatic renal cell carcinoma (RCC) received on a 3+3 trial design escalating doses of s.c. GM-CSF, IL-2 and IFN-α. Dose-limiting toxicities (DLTs) during the first 6-week cycle were used to determine the MTD. A phase II trial was then initiated to determine clinical activity., Results: A total of sixty patients were enrolled in the study (phase I = 31; phase II = 29). Two DLTs were observed (G3 nausea/vomiting and fatigue) and the MTD was determined to be GM-CSF 5.0 µg/kg/day, IL-2 9.0 mIU/m(2)/day and IFN-α 5.0 mU/m(2)/day. Patients received a median (range) of four (one to 11) cycles of therapy. G3 adverse events were reported in 10 of 31 (32%) patients. The overall response rate was 20% (one complete response and 11 partial responses), including patients who were rendered free of disease with surgery. The median progression-free survival and overall survival were 6.0 and 23.4 months, respectively., Conclusions: Immunotherapy with concurrent s.c. GM-CSF, IL-2 and IFN-α is generally well tolerated. The overall response rate observed with this combination continues to show the efficacy of immunotherapy in a selected group of metastatic RCC patients., (© 2010 THE AUTHORS. BJU INTERNATIONAL © 2010 BJU INTERNATIONAL.)

Background: An important goal of noncurative therapy for metastatic renal cell carcinoma (mRCC) is tumor burden (TB) control. However, to the authors' knowledge, the impact of TB characteristics on clinical outcome has not been studied in patients with mRCC who were treated with vascular endothelial growth factor-targeted therapy., Methods: Patients with clear cell mRCC who were treated with sunitinib between June 2004 and October 2007 were retrospectively identified. Computed tomography scans were re-reviewed from baseline, at the time of maximal TB shrinkage (TS) while receiving sunitinib, and at the time of progressive disease (PD). Measurements were recorded as per Response Evaluation Criteria In Solid Tumors (RECIST)., Results: A total of 69 patients were identified. The majority (54%) were classified as being of favorable risk using Cleveland Clinic Foundation Tyrosine Kinase Inhibitor (CCF TKI) risk group criteria. All patients underwent prior nephrectomy and 77% received prior systemic therapy. There were a median of 8 metastatic deposits across all organs (range, 1-27 deposits). The median TB at the initiation of therapy was 14.0 cm (range, 3.0 cm-42.2 cm). On multivariable analysis, baseline characteristics of disease confined to above the diaphragm (P = .03) and a total TB <13 cm (P = .09) were found to be independent positive predictors of progression-free survival. A+ baseline, total number of metastases <10 (P < .001) and TB above the diaphragm <6.5 cm (P = .05) were found to be independent positive predictors of overall survival (OS). Increased TS while receiving sunitinib was found to be significantly associated with OS (P < .001). At the time of PD, tumor location and pattern of disease progression were not found to be associated with survival as measured from the date of PD. However, total TB (P = .003) and total number of metastatic deposits (≤12 vs >12; P < .001) were found to be significant predictors of survival after PD., Conclusions: The results of the current study indicate that TB characteristics are associated with clinical outcome in patients with mRCC who are treated with sunitinib., (Copyright © 2010 American Cancer Society.)

The multitargeted tyrosine-kinase inhibitor sunitinib has emerged as one of the standards of care for good- and intermediate-risk metastatic renal cell carcinoma. Although generally associated with acceptable toxicity, sunitinib exhibits a novel and distinct toxicity profile that requires monitoring and management. Fatigue, diarrhea, anorexia, oral changes, hand-foot syndrome and other skin toxicity, thyroid dysfunction, myelotoxicity, and hypertension seem to be the most common and clinically relevant toxicities of sunitinib. Drug dosing and treatment duration are correlated with response to treatment and survival. Treatment recommendations for hypertension have been published but, currently, no standard guidelines exist for the management of noncardiovascular side effects. To discuss the optimal management of noncardiovascular side effects, an international, interdisciplinary panel of experts gathered in November 2009. Existing literature on incidence, severity, and underlying mechanisms of side effects as well as on potential treatment options were carefully reviewed and discussed. On the basis of these proceedings and the thorough review of the existing literature, recommendations were made for the monitoring, prevention, and treatment of the most common noncardiovascular side effects and are summarized in this review. The proactive assessment and consistent and timely management of sunitinib-related side effects are critical to ensure optimal treatment benefit by allowing appropriate drug dosing and prolonged treatment periods.

Objective: To determine if the fractional percentage of tumour volume (FPTV) removed with debulking nephrectomy was associated with progression-free survival (PFS) after subsequent targeted therapy, as a debulking nephrectomy is the standard of care in metastatic renal cell carcinoma (mRCC), but there are few data., Patients and Methods: The Cleveland Clinic Taussig Cancer Institute Urologic Oncology database was retrospectively reviewed from 2005 to 2008 to identify patients with mRCC who had undergone debulking nephrectomy followed by vascular endothelial growth factor (VEGF)-targeted therapy, defined as sunitinib-, sorafenib- or bevacizumab-based therapy. FPTV was calculated as the largest diameter of the primary tumour divided by the total tumour burden (as per the Response Evaluation Criteria in Solid Tumors, RECIST) through investigator re-review of imaging. PFS was defined from the start date of systemic therapy to disease progression per RECIST criteria., Results: Forty-six patients were identified (80% men, median age 61 years, all clear cell histology and 67% with an Eastern Cooperative Oncology Group performance status of 0). Patients received treatment with bevacizumab ± interleukin-2 (18), sunitinib (14), sorafenib (11) or sunitinib + bevacizumab (three). The median diameter of the primary tumour was 10.0 cm. The median (range) FPTV removed was 95 (80-99)%. In univariable analysis, the FPTV removed (P = 0.002) and normal haemoglobin level (P = 0.04) were associated with improved PFS. In multivariable analysis, the FPTV removed (P < 0.001), male gender (P = 0.001) and corrected calcium (P = 0.05) were independent predictors of PFS., Conclusion: A greater percentage of tumour burden removed at debulking nephrectomy is significantly associated with improved PFS on subsequent VEGF-targeted systemic therapy., (© 2010 THE AUTHORS. JOURNAL COMPILATION © 2010 BJU INTERNATIONAL.)

Treatment options for renal cell carcinoma have changed dramatically since 2005 when the U.S. Food and Drug Administration approved six new therapies. These agents inhibit pathways relevant in the pathogenesis of renal cell carcinoma, interfering with tumor angiogenesis, cell progression, and metastasis. Understanding the pharmacology of these agents is necessary for clinicians to provide appropriate patient education, assure adherence with the treatment plan, and facilitate early identification and intervention for side effects. These activities will provide positive clinical outcomes.

The availability of vascular endothelial growth factor and multikinase inhibitors (MKIs) has enhanced treatment strategies for patients with advanced kidney cancer. Side effects associated with the agents include dermatologic toxicities, gastrointestinal toxicities, and hematologic and metabolic abnormalities that may interfere with treatment adherence. Nurses play a key role in managing side effects associated with emerging therapies. This article presents a case study to illustrate side-effect management strategies for patients receiving MKIs for the treatment of advanced renal cell carcinoma.

Kidney cancer is most often diagnosed incidentally at the time of radiographic imaging for other complaints. Although numerous improvements and greater use of screening measures have occurred in the setting of renal cell carcinoma (RCC), screening for this disease is usually only carried out for patients who have been identified as having one of the known genetic lineages linked with specific RCC subtypes. This article reviews key concepts in the screening, diagnosis, and prognosis of patients with RCC.

Purpose: To investigate the efficacy and safety of axitinib, an oral, potent, and selective inhibitor of vascular endothelial growth factor (VEGF) receptors 1, 2, and 3 in patients with metastatic renal cell carcinoma (mRCC) refractory to prior therapies that included, but were not limited to, sorafenib., Patients and Methods: In this multicenter, open-label, phase II study, patients with sorafenib-refractory mRCC received a starting dose of axitinib 5 mg orally twice daily. A one-arm, single-stage design was used to estimate the primary end point of objective response rate (ORR), defined by RECIST (Response Evaluation Criteria in Solid Tumors). Secondary end points included safety, duration of response, progression-free survival (PFS), overall survival (OS), and patient-reported outcomes., Results: Of 62 patients recruited, 100% had received prior sorafenib, and 74.2% had received two or more prior systemic treatments. The axitinib dose was titrated to greater than 5 mg twice daily in 53.2% of patients, and 35.5% of patients had the dose modified to less than 5 mg twice daily. In 62 patients evaluable for response, the ORR was 22.6%, and the median duration of response was 17.5 months. Median PFS and OS times were 7.4 months (95% CI, 6.7 to 11.0 months) and 13.6 months (95% CI, 8.4 to 18.8 months), respectively. All-causality grade 3 to 4 adverse events included hand-foot syndrome (16.1%), fatigue (16.1%), hypertension (16.1%), dyspnea (14.5%), diarrhea (14.5%), dehydration (8.1%), and hypotension (6.5%)., Conclusion: Axitinib has antitumor activity in patients with mRCC refractory to prior VEGF-targeted therapy, including sorafenib. Toxicities were mild to moderate and were manageable. A randomized, phase III trial to compare axitinib with sorafenib in patients who have mRCC refractory to one prior first-line therapy regimen is underway.

Purpose: Immune dysfunction reported in renal cell carcinoma (RCC) patients may contribute to tumor progression. Myeloid-derived suppressor cells (MDSC) represent one mechanism by which tumors induce T-cell suppression. Several factors pivotal to the accumulation of MDSC are targeted by the tyrosine kinase inhibitor, sunitinib. The effect of sunitinib on MDSC-mediated immunosuppression in RCC patients has been investigated., Experimental Design: Patient peripheral blood levels of MDSC and regulatory T-cell (Treg) and T-cell production of IFN-gamma were evaluated before and after sunitinib treatment. Correlations between MDSC and Treg normalization as well as T-cell production of IFN-gamma were examined. The in vitro effect of sunitinib on patient MDSC was evaluated., Results: Metastatic RCC patients had elevated levels of CD33(+)HLA-DR(-) and CD15(+)CD14(-) MDSC, and these were partially overlapping populations. Treatment with sunitinib resulted in significant reduction in MDSC measured by several criteria. Sunitinib-mediated reduction in MDSC was correlated with reversal of type 1 T-cell suppression, an effect that could be reproduced by the depletion of MDSC in vitro. MDSC reduction in response to sunitinib correlated with a reversal of CD3(+)CD4(+)CD25(hi)Foxp3(+) Treg cell elevation. No correlation existed between a change in tumor burden and a change in MDSC, Treg, or T-cell production of IFN-gamma. In vitro addition of sunitinib reduced MDSC viability and suppressive effect when used at >/=1.0 microg/mL. Sunitinib did not induce MDSC maturation in vitro., Conclusions: Sunitinib-based therapy has the potential to modulate antitumor immunity by reversing MDSC-mediated tumor-induced immunosuppression.

Purpose: Metastatic renal cell carcinoma (mRCC) with sarcomatoid differentiation is an aggressive disease that is associated with poor outcomes to chemotherapy or immunotherapy. The utility of vascular endothelial growth factor (VEGF)-targeted therapy in patients with this disease is unknown., Patients and Methods: Patients who had mRCC with sarcomatoid features in the primary tumor and who were treated with VEGF-targeted therapy were retrospectively identified. Pathology slides were reviewed to determine the percentage of sarcomatoid differentiation. Objective response rate, percentage of tumor burden shrinkage, progression-free survival (PFS), and overall survival (OS) were determined., Results: Forty-three patients who had sarcomatoid mRCC were identified. The median percentage of sarcomatoid features was 14% (range, 3% to 90%). Patients were treated with either sunitinib (49%), sorafenib (28%), bevacizumab (19%), or sunitinib plus bevacizumab (5%). Partial responses were observed in eight patients (19%); 21 patients (49%) had stable disease; and 14 patients (33%) had progressive disease as their best response. Partial responses were limited to patients who had underlying clear-cell histology and less than 20% sarcomatoid elements. Median tumor shrinkage was -2% (range, -85% to 127%), and 53% achieved some degree of tumor shrinkage on therapy. Median PFS and OS were estimated to be 5.3 months and 11.8 months, respectively., Conclusion: Patients who have mRCC and sarcomatoid differentiation can demonstrate objective responses and tumor shrinkage to VEGF-targeted therapy. Patients who have clear-cell histology and a lower percentage of sarcomatoid differentiation may have better outcomes with VEGF-targeted therapy.

Purpose: Immune dysfunction is well documented in renal cell carcinoma (RCC) patients and likely contributes to tumor evasion. This dysfunction includes a shift from a type-1 to a type-2 T-cell cytokine response and enhanced T-regulatory (Treg) cell expression. Given the antitumor activity of select tyrosine kinase inhibitors such as sunitinib in metastatic RCC (mRCC) patients, it is relevant to assess their effect on the immune system., Experimental Design: Type-1 (IFNgamma) and type-2 (interleukin-4) responses were assessed in T cells at baseline and day 28 of treatment with sunitinib (50 mg/d) by measuring intracellular cytokines after in vitro stimulation with anti-CD3/anti-CD28 antibodies., Results: After one cycle of treatment, there was a significant increase in the percentage of IFNgamma-producing T cells (CD3(+), P < 0.001; CD3(+)CD4(+), P = 0.001), a reduction in interleukin-4 production (CD3(+) cells, P = 0.05), and a diminished type-2 bias (P = 0.005). The increase in type-1 response may be partly related to modulation of Treg cells. The increased percentage of Treg cells noted in mRCC patients over healthy donors (P = 0.001) was reduced after treatment, although not reaching statistical significance. There was, however, an inverse correlation between the increase in type-1 response after two cycles of treatment and a decrease in the percentage of Treg cells (r = -0.64, P = 0.01). In vitro studies suggest that the effects of sunitinib on Treg cells are indirect., Conclusions: The demonstration that sunitinib improved type-1 T-cell cytokine response in mRCC patients while reducing Treg function provides a basis for the rational combination of sunitinib and immunotherapy in mRCC.

Background: Sunitinib and sorafenib are small molecules that inhibit the vascular endothelial growth factor and related receptors with substantial clinical activity reported in metastatic renal cell carcinoma (RCC). Cytopenia and macrocytosis have been described in patients treated with these agents., Methods: A retrospective review of all patients with metastatic RCC who were treated with sunitinib or sorafenib for at least 3 months at the Cleveland Clinic Taussig Cancer Institute was undertaken. Complete blood count (CBC) data including red blood cell indices were recorded at baseline, after 3 months of therapy, and at the end of treatment., Results: A total of 61 patients were treated with sunitinib and 37 patients were treated with sorafenib with available CBC data. In patients treated with sunitinib, the median corpuscular volume (MCV) increased significantly at 3 months compared with baseline (median increase of 5.1 femtoliters [fL]; P < .001) and continued to increase throughout treatment. Patients who developed hypothyroidism had a larger MCV increase at 3 months than patients who remained euthyroid (P = .06), although macrocytosis was observed in patients without hypothyroidism. Ten patients discontinued sunitinib therapy, and the MCV decreased in all patients within 2 to 4 months, without further intervention. Bone marrow analysis of 4 patients revealed a hypocellular bone marrow with trilineage hematopoiesis and no evidence of metastasis. There was no evidence of folate or vitamin B12 deficiency. In contrast to sunitinib, there was no change in the MCV for patients treated with sorafenib., Conclusions: Macrocytosis was a common occurrence after treatment with sunitinib but not sorafenib in patients with metastatic RCC. Sunitinib-induced macrocytosis is reversible with drug discontinuation., ((c) 2008 American Cancer Society.)

Purpose: The von Hippel-Lindau (VHL) gene is often inactivated (by mutation or promoter hypermethylation) in renal cell carcinoma but the relation to therapeutic outcome is unclear., Materials and Methods: Patients with metastatic clear cell renal cell carcinoma with available baseline tumor samples who received vascular endothelial growth factor targeted therapy were included in analysis. Patient characteristics, VHL gene status and clinical outcome were documented. Our primary end point was to test for response rate in relation to VHL inactivation. Progression-free survival and overall survival in relation to VHL status were investigated as secondary end points., Results: A total of 123 patients were evaluable. Response rate, median progression-free survival and median overall survival were 37% (95% CI 28-46), 10.8 (95% CI 7.7-14.8) and 29.8 (CI not estimable) months, respectively. Patients with VHL inactivation had a response rate of 41% vs 31% for those with wild-type VHL (p = 0.34). Patients with loss of function mutations (frameshift, nonsense, splice and in-frame deletions/insertions) had a 52% response rate vs 31% with wild-type VHL (p = 0.04). On multivariate analysis the presence of a loss of function mutation remained an independent prognostic factor associated with improved response. Progression-free survival and overall survival were not significantly different based on VHL status., Conclusions: To our knowledge this is the largest analysis investigating the impact of VHL inactivation on the outcome of vascular endothelial growth factor targeted agents in metastatic renal cell carcinoma. We did not find a statistically significant increase in response to vascular endothelial growth factor targeted agents in patients with VHL inactivation. Loss of function mutations identified a population of patients with a greater response. Investigation of downstream markers is under way.

Purpose: Pegylated interferon alpha-2b (PEG-Intron) is a conjugate of polyethylene glycol (PEG) and interferon alpha-2b, has a prolonged half-life, and an increased area under the curve (AUC) for interferon alpha-2b. The combination of PEG-Intron with recombinant interleukin-2 (rIL-2) was investigated in a phase 1 trial. To determine the maximal tolerable dose (MTD) and preliminary efficacy of concurrent subcutaneous (SC) administration of PEG-Intron and rIL-2 in patients with metastatic renal cell carcinoma (RCC)., Methods: Cohorts of 3-6 patients received escalating doses of PEG-Intron (I-1.5, II- 1.5, III-3.0, IV-3.0, V-4.5 microg/kg SC) given weekly in combination with rIL-2 administered three times weekly (TIW) for 6 weeks. rIL-2 dose levels were escalated in weeks 1 and 4 (I-10.0, II-15.0, III-15.0, IV-20.0, V-20.0 MIU/m(2) SC), and 5.0 MIU/m(2) SC TIW was administered during weeks 2, 3, 5 and 6., Results: Thirty-four patients (24 men; 10 women) were accrued at dose levels I (n = 4), II (n = 4), III (n = 6), IV (n = 14), and V (n = 6) between October 2000 and October 2002. All but one patient had prior nephrectomy (n = 33) and all but one patient (97%) had received no prior systemic therapy. Patients received a median of four cycles of treatment (range 1-9). Dose limiting toxicity occurred at dose level V and included grade 4 neutropenia and hypoxemia. A partial response was found in 5 pts (15%). Median progression-free and overall survival were 9.0 (95% C.I. 5.6-13.1 months) and 31.9 months (95% C.I. 17.2-61.9 months), respectively., Conclusion: The combination of PEG-Interferon and SC rIL-2 can be administered with acceptable toxicity.

Purpose: Antiangiogenic therapy with sunitinib and sorafenib has become the standard of care for patients with advanced renal cell carcinoma. However, the clinical benefit of these agents after prior antiangiogenic therapy has not been defined. Currently, several agents with a putative antiangiogenic mechanism exist and they are often being used in sequence with little to no data regarding activity in a second line or later setting., Materials and Methods: Patients with advanced renal cell carcinoma currently being treated with either sunitinib or sorafenib after receiving 1 or more prior antiangiogenic agent(s) were investigated in a retrospective analysis. Time to progression and the overall response rate by Response Evaluation Criteria in Solid Tumors were evaluated., Results: Thirty patients receiving current sunitinib (16 patients) or sorafenib (14 patients) were identified. Patients received 1 or more prior antiangiogenic therapies: thalidomide, lenalidomide, bevacizumab, volociximab, AG13736, sorafenib or sunitinib. Of 16 patients treated with sunitinib 13 had some degree of tumor shrinkage, including 9 with a partial response by Response Evaluation Criteria in Solid Tumors. Of 14 patients treated with sorafenib 10 had some degree of tumor shrinkage, including 1 with a partial response. The median time to progression for the entire cohort was 10.4 months., Conclusions: Significant antitumor activity is observed when sorafenib or sunitinib are used in patients who have failed prior therapy with an antiangiogenic agent. Prior response to an antiangiogenic agent does not appear to predict subsequent clinical benefit to either sunitinib or sorafenib.

Sunitinib is a tyrosine kinase inhibitor with activity against vascular endothelial growth factor (VEGF) receptor and platelet-derived growth factor receptor recently approved by the FDA for the treatment of advanced renal cell carcinoma (RCC). Complete responses (CRs) to sunitinib have been documented in the literature. However, a detailed description and analysis of these patients is lacking. Seventy-four patients receiving sunitinib at the Cleveland Clinic in first-, second-, and third-line clinical trials were reviewed to determine the number of patients with Response Evaluation Criteria in Solid Tumors (RECIST)-defined CRs and patients who have achieved near CRs (nCRs) with a > 90% reduction in composite tumor volume or residual disease of 22 months while on maintenance sunitinib. The patients who obtained CRs had nonbulky pulmonary metastases, had favorable or intermediate Memorial Sloan-Kettering Cancer Center risk profiles, were treated with sunitinib in the first-line setting, and had a significant reduction in composite tumor measurements within the first 2 cycles. Two additional patients achieved nCRs, including a patient who had previously progressed on bevacizumab. Finally, 1 patient achieved sufficient downstaging and reduction of tumor volume such that the remaining lesion could be excised to produce a surgical CR. Sunitinib is capable of producing durable CRs in patients with cytokine-naive, metastatic RCC who have nonbulky pulmonary metastases. Additionally, nCRs can be seen despite nonpulmonary metastatic sites and previous VEGF-targeted therapy.

Diagnosis of renal cell carcinoma (RCC) frequently occurs at advanced stages, severely limiting the success of treatment, and median survival is barely more than a year. Previously, treatment of renal cancer was limited to nephrectomy or immunotherapy (interleukin or interferon-alpha), which was effective in a small subset of patients but often was accompanied by severe side effects. New orally administered targeted therapies have become available, offering broader benefits to patients with advanced RCC. Sorafenib is an oral, multikinase inhibitor recently approved by the U.S. Food and Drug Administration as treatment for advanced RCC based on its extension of median progression-free survival from 12-24 weeks. Oncology nurses must ensure patient adherence and manage side effects of emerging treatments. This article reviews the management of skin rash, hand-foot skin reaction, hypertension, diarrhea, and fatigue in patients receiving sorafenib. In addition, a case study of a patient receiving sorafenib is presented.

Background: Therapy targeted against the vascular endothelial growth factor (VEGF) pathway is a standard of care for patients with metastatic renal cell carcinoma (RCC). The identification of patients who are more likely to benefit from these agents is warranted., Methods: In total, 120 patients with metastatic clear-cell RCC received bevacizumab, sorafenib, sunitinib, or axitinib on 1 of 9 prospective clinical trials at the Cleveland Clinic. Clinical features associated with outcome were identified by univariate analysis; then, a stepwise modeling approach based on Cox proportional hazards regression was used to identify independent prognostic factors and to form a model for progression-free survival (PFS). A bootstrap algorithm was used to provide internal validation., Results: The overall median PFS was 13.8 months, and the objective response according to the Response Criteria in Solid Tumors was 34%. Multivariate analysis identified time from diagnosis to current treatment <2 years; baseline platelet and neutrophil counts >300 K/microL and >4.5 K/microL, respectively; baseline corrected serum calcium <8.5 mg/dL or >10 mg/dL; and initial Eastern Cooperative Oncology Group performance status >0 as independent, adverse prognostic factors (PF) for PFS. Three prognostic subgroups were formed based on the number of adverse prognostic factors present. The median PFS in patients with 0 or 1 adverse prognostic factor was 20.1 months compared with 13 months in patients with 2 adverse prognostic factors and 3.9 months in patients with >2 adverse prognostic factors., Conclusions: Five independent prognostic factors for predicting PFS were identified and were used to categorize patients with metastatic RCC who received VEGF-targeted therapies into 3 risk groups. These prognostic factors can be incorporated into patient care and clinical trials that use such novel, VEGF-targeted agents., ((c) 2007 American Cancer Society.)

Sunitinib is an inhibitor of the vascular endothelial growth factor and platelet-derived growth factor receptors, and it has antitumor activity in metastatic renal cell carcinoma and gastrointestinal stromal tumors. To further investigate the fatigue associated with sunitinib therapy, thyroid function tests were performed on patients with metastatic renal cell carcinoma who were receiving sunitinib. Seventy-three patients with metastatic renal cell carcinoma were treated with sunitinib at the Cleveland Clinic Taussig Cancer Center, and 66 of them had thyroid function test results available. Fifty-six (85%) of the 66 patients had one or more abnormality in their thyroid function test results, consistent with hypothyroidism, and 47 (84%) of the 56 patients with abnormal thyroid function tests had signs and/or symptoms possibly related to hypothyroidism. Thyroid hormone replacement was undertaken in 17 patients, and symptoms improved in nine of them. Thyroid function test abnormalities appear to be common in patients with metastatic renal cell carcinoma treated with sunitinib, and routine monitoring is warranted.

Background: It has been suggested that thrombocytosis, as defined by a platelet count >400,000/microL, is a negative predictor for survival among patients with metastatic renal cell carcinoma. However, this has not been a uniform finding., Methods: To address this issue, retrospective analysis of 700 previously untreated patients entering on institution review board-approved phase 1, 2, or 3 clinical trials in the United States and Europe was conducted between 1982 and 2002., Results: Thrombocytosis was present at study entry in 25% of patients. Median baseline platelet count was 304,000/microL (range, 86-1,420,000/microL). Eighty-seven percent of patients died with a median survival of 13.0 months. Median follow-up for patients not known to have died was 2.4 years. On univariate analysis, patients with elevated platelet counts had significantly shorter survival than patients with normal platelet counts; median survivals of 8.4 and 14.6 months, respectively, P < .001. However, platelet count was associated with several clinical and biochemical factors, including gender, age, performance status, time from diagnosis to study entry, prior radiotherapy or nephrectomy, presence of liver metastasis, number of metastatic sites, amount of hemoglobin, white blood cell count, amount of lactate dehydrogenase, and amount of serum alkaline phosphatase. Several of these factors have previously been reported as prognostic indicators for survival, and, therefore, multivariable analyses were conducted to determine whether thrombocytosis is an independent predictor of survival. After adjusting for multiple factors, thrombocytosis continued to impact negatively on survival, P < .001., Conclusions: Thrombocytosis was found to be an independent prognostic factor for survival in patients with metastatic renal cell carcinoma., (2006 American Cancer Society)

Background: The treatment of advanced renal cell cancer remains unsatisfactory, therefore new combination regimens such as thalidomide and IL-2 are of interest. A phase I trial of SC IL-2 and oral thalidomide was performed to identify the toxicity, maximum tolerated dose (MTD) and preliminary clinical activity of this regimen., Methods: 33 patients with advanced/metastatic RCC were enrolled. An established 8-week outpatient schedule of subcutaneously administered IL-2 in escalating doses, days 1-5, for 6 weeks with a 2 week rest was utilized with daily oral thalidomide. Cohorts of 4-6 patients were treated at 4 dose levels., Results: Toxicity was moderate to severe and related to dose level. All patients developed fever, chills and fatigue. 29/33 patients developed < or = Grade 2 desquamation of hands and feet and/or rash. Dose limiting toxicity (DLT) included Grade 3 neutropenia and pulmonary embolus. The maximum tolerated dose (MTD) of IL-2 and thalidomide was 9.0 MIU/m2 s.c. days 1-5, weeks 1 to 6 and 100 mg p.o. daily, respectively. A median of 2 cycles of therapy was administered (range 1-9). 2/33 patients responded (1 CR--prior IL-2 therapy, 1 PR--no prior therapy) with an overall response of 6% (95% CI, 1-20%). One minimal response was converted to a surgical CR (remains disease free at 24 + months)., Conclusion: Outpatient administration of IL-2 and thalidomide is possible with acceptable toxicity. Further evaluation of this regimen is underway.

Background: A pilot study was conducted to investigate the toxicity and tolerance to low-dose subcutaneous interleukin-2 (IL-2) for patients with resected renal cell carcinoma (RCC) at high risk for recurrent disease (TNM stages III and IV resected distant metastases)., Patients and Methods: Patients with surgically resected locally advanced (T3-4 or N1-2) or metastatic RCC were randomly assigned to 1 of 4 treatment groups that received different dose levels and schedules of subcutaneous IL-2 as follows: dose level 1, 4 MIU/m2 per day, every other week for 24 weeks (n = 10); dose level 2, 8 MIU/m2 per day, every other week for 24 weeks (n = 9); dose level 3, 4 MIU/m2 per day, weeks 1-4, 9-12, and 17-20 (n = 11); and dose level 4, 8 MIU/m2 per day, weeks 1-4, 9-12, and 17-20 (n = 10). Interleukin-2 was administered in 2 daily doses on days 1-5 of each week indicated. A dose level was considered tolerable if no more than 2 patients experienced grade 3/4 toxicity., Results: Forty-one patients were entered in the study and 40 were evaluable for toxicity. Therapy was well tolerated at all dose levels and schedules, with most patients (98%) experiencing mild-to-moderate constitutional symptoms. Grade 3/4 toxicity was seen in 8 patients (20%). Interleukin-2 dose reductions were required in 7 patients, and no patient discontinued therapy secondary to toxicity. Of 39 patients evaluable for efficacy, 31 have experienced relapse (79%), and 15 have died (38%). Median survival was 1.4 years, and the 3-year disease-free survival rate was 33%. Median overall survival has not been reached; however, the 3-year survival rate was 70%. There was no statistically significant difference between any of the treatment arms with respect to disease-free survival or 3-year survival (P > 0.54 and P >or= 0.09 for all pairwise comparisons), schedules (dose level 1/2 vs. 3/4; P = 0.46 and P = 0.5), or dose of IL-2 administered (dose level 1/3 vs. 2/4; P = 0.99 and P = 0.1)., Conclusion: Subcutaneous IL-2 was well tolerated for 6 months in patients with surgically resected RCC at high risk of recurrence. Future adjuvant trials in this setting are not likely to include IL-2 in view of the clinical efficacy and favorable toxicity profiles of selected multitargeted kinase inhibitors.

Purpose: To validate the Motzer et al prognostic factors model for survival in patients with previously untreated metastatic renal cell carcinoma (RCC) and to identify additional independent prognostic factors., Patients and Methods: Data were collected on 353 previously untreated metastatic RCC patients enrolled onto clinical trials between 1987 and 2002., Results: Four of the five prognostic factors identified by Motzer were independent predictors of survival. In addition, prior radiotherapy and presence of hepatic, lung, and retroperitoneal nodal metastases were found to be independent prognostic factors. Using the number of metastatic sites as surrogate for individual sites (none or one v two or three sites), Motzer's definitions of risk groups were expanded to accommodate these two additional prognostic factors. Using this expanded criteria, favorable risk is defined as zero or one poor prognostic factor, intermediate risk is two poor prognostic factors, and poor risk is more than two poor prognostic factors. According to Motzer's definitions, 19% of patients were favorable risk, 70% were intermediate risk, and 11% were poor risk; median overall survival times for these groups were 28.6, 14.6, and 4.5 months, respectively (P < .0001). Using the expanded criteria, 37% of patients were favorable risk, 35% were intermediate risk, and 28% were poor risk; median overall survival times of these groups were 26.0, 14.4, and 7.3 months, respectively (P < .0001)., Conclusion: These data validate the model described by Motzer et al. Additional independent prognostic factors identified were prior radiotherapy and sites of metastasis. Incorporation of these additional prognostic factors into the Motzer et al model can help better define favorable risk, intermediate risk, and poor risk patients.

Purpose/objectives: To review standard and investigational treatments in advanced renal cell carcinoma, with a focus on thalidomide., Data Sources: Published articles, conference proceedings, treatment guidelines, and textbooks., Data Synthesis: The prognosis for advanced renal cell carcinoma when treated with standard regimens is poor; therefore, new treatments are needed., Conclusions: Treatment with thalidomide, alone and in combination with other therapies, may improve survival for patients with advanced renal cell carcinoma., Implications for Nursing: Proactive management of adverse effects associated with thalidomide, alone and in combination, may increase patient tolerance and compliance.