Adjuvant therapy in patients with sarcomatoid renal cell carcinoma: post hoc analysis from Eastern Cooperative Oncology Group-American College of Radiology Imaging Network (ECOG-ACRIN) E2805.

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

Angiogenic Factor and Cytokine Analysis among Patients Treated with Adjuvant VEGFR TKIs in Resected Renal Cell Carcinoma.

PURPOSE: The use of VEGFR TKIs for the adjuvant treatment of renal cell carcinoma (RCC) remains controversial. We investigated the effects of adjuvant VEGFR TKIs on circulating cytokines in the ECOG-ACRIN 2805 (ASSURE) trial. EXPERIMENTAL DESIGN: Patients with resected high-risk RCC were randomized to sunitinib, sorafenib, or placebo. Plasma from 413 patients was analyzed from post-nephrectomy baseline, 4 weeks, and 6 weeks after treatment initiation. Mixed effects and Cox proportional hazards models were used to test for changes in circulating cytokines and associations between disease-free survival (DFS) and cytokine levels. RESULTS: VEGF and PlGF increased after 4 weeks on sunitinib or sorafenib (P < 0.0001 for both) and returned to baseline at 6 weeks on sunitinib (corresponding to the break in the sunitinib schedule) but not sorafenib (which was administered continuously). sFLT-1 decreased after 4 weeks on sunitinib and 6 weeks on sorafenib (P < 0.0001). sVEGFR-2 decreased after both 4 and 6 weeks of treatment on sunitinib or sorafenib (P < 0.0001). Patients receiving placebo had no significant changes in cytokine levels. CXCL10 was elevated at 4 and 6 weeks on sunitinib and sorafenib but not on placebo. Higher baseline CXCL10 was associated with worse DFS (HR 1.41 per log increase in CXCL10, Bonferroni-adjusted P = 0.003). This remained significant after adjustment for T-stage, Fuhrman grade, and ECOG performance status. CONCLUSIONS: Among patients treated with adjuvant VEGFR TKIs for RCC, drug-host interactions mediate changes in circulating cytokines. Elevated baseline CXCL10 was associated with worse DFS. Studies to understand functional consequences of these changes are under way.

Association between age and sex and mortality after adjuvant therapy for renal cancer.

BACKGROUND: In phase 3 trials of patients with resected high-risk renal cell carcinoma, adjuvant sunitinib has demonstrated no overall survival (OS) benefit, an uncertain disease-free survival (DFS) benefit, and increased toxicity versus placebo. To identify patients who may derive benefit or harm from adjuvant therapy, the authors assessed the effects of age and sex on treatment outcomes in the phase 3 Adjuvant Sorafenib or Sunitinib for Unfavorable Renal Cancer (ASSURE) trial. METHODS: The authors conducted a post hoc subgroup analysis of age and sex among patients in the ASSURE trial. Adjusted hazard ratios (HRs) for OS and DFS were evaluated with sunitinib or sorafenib versus placebo in 4 patient subgroups defined by sex and median age at the time of the study. RESULTS: Sunitinib treatment was associated with decreased OS (HR, 2.21; 95% confidence interval, 1.29-3.80) among women aged >56 years, but not in women aged ≤56 years or men of any age. Similar associations with age and sex were observed for DFS, but these were not statistically significant (women aged >56 years: HR, 1.41 [95% confidence interval, 0.94-2.10]). No such association was found for sorafenib. The interaction by age and sex on mortality was found to be statistically significant for sunitinib (P = .01), but not sorafenib (P = .10). CONCLUSIONS: Adjuvant sunitinib may increase mortality among older women with renal cell carcinoma. Given the recent approval of adjuvant sunitinib for patients with high-risk resected renal cell carcinoma, additional studies are needed to confirm these findings.

Adjuvant Treatment for High-Risk Clear Cell Renal Cancer: Updated Results of a High-Risk Subset of the ASSURE Randomized Trial.

IMPORTANCE: Given recently published results of a 750-patient adjuvant sunitinib trial showing improved disease-free survival (DFS), the appropriate strategy for treating high-risk patients is unclear. We sought to determine whether there is improved disease-free survival benefit to taking the active drug in patients with high-risk (pT3, pT4, node-positive) clear cell renal cancer (ccRCC) in the ASSURE trial (adjuvant sunitinib or sorafenib vs placebo in resected unfavorable renal cell carcinoma [RCC]), the largest adjuvant trial published to date. OBJECTIVE: To evaluate DFS and overall survival (OS) in ccRCC high-risk patients randomized to sunitinib or sorafenib vs placebo among patients with stages comparable to other high-risk adjuvant trials. DESIGN, SETTING, AND PARTICIPANTS: The DFS and OS at 10 years postactivation were calculated for 1069 patients in US and Canadian cooperative groups with high-risk patients who had ccRCC histology and pT3, pT4, or node-positive disease accrued between 2006 and 2010 to the double-blind randomized placebo-controlled phase 3 trial. Outcome analyses by dose quartiles of these patients receiving sunitinib or sorafenib were also performed. INTERVENTIONS: Patients received 1 year of adjuvant sunitinib (50 mg), sorafenib (800 mg) daily, or equivalent placebo. The study was amended for patient intolerance to sunitinib (37.5 mg), sorafenib (400 mg) daily, or equivalent placebo with mandatory dose escalation if no serious adverse effects were experienced. MAIN OUTCOMES AND MEASURES: Disease-free survival, defined as time from randomization to recurrence, second primary cancer, or death. RESULTS: Of 1069 patients, 358 (243 [67.9%] men, 115 [32.1%] women) received sunitinib, 355 (248 [69.9%] men, 107 [30.1%] women) received sorafenib, and 356 (254 [71.3%] men, 102 [28.7%] women) received placebo as adjuvant therapy. The mean (SD) age for each group was 58.3 (10.6) years, 56.8 (10.3) years, and 57.5 (10.4) years, respectively. Five-year DFS rates were 47.7%, 49.9%, and 50.0%, respectively for sunitinib, sorafenib, and placebo (HR, 0.94 for sunitinib vs placebo; and HR, 0.90; 97.5% CI, 0.71-1.14 for sorafenib vs placebo), with 5-year OS of 75.2%, 80.2%, and 76.5% (HR, 1.06; 97.5% CI, 0.78-1.45; P = .66, sunitinib vs placebo; and HR, 0.80; 97.5% CI, 0.58-1.11; P = .12 for sorafenib vs placebo). There was no difference by dose quartile. CONCLUSIONS AND RELEVANCE: Neither prognostic category of the tumor nor dose intensity of therapy altered the lack of difference in DFS or OS in this population of patients with high-risk ccRCC. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00326898.

Pure Red Cell Aplasia Following Interleukin-2 Therapy.

A 61-year-old woman with metastatic renal cell carcinoma underwent systemic treatment with high-dose interleukin-2 (IL-2). Anemia requiring transfusion of 1 unit of packed red blood cells (PRBCs) was required during the second week of IL-2 therapy. One month following completion of high-dose IL-2 treatment, she was hospitalized for severe, symptomatic anemia and received 5 units of PRBCs. She was referred back for evaluation. A complete hematologic evaluation was performed including antiviral serology, evaluation for hemolysis, complete iron studies, and finally bone marrow aspiration and biopsy. The diagnosis was pure red cell aplasia, and no inciting viral cause could be ascertained. She required PRBCs for 5 months following IL-2 therapy. It was concluded that IL-2 was the cause of her red cell aplasia. This subsequently resolved spontaneously, and she had normal hemoglobin and hematocrit, respectively, 1 and 2 years after treatment.

Adjuvant sunitinib or sorafenib for high-risk, non-metastatic renal-cell carcinoma (ECOG-ACRIN E2805): a double-blind, placebo-controlled, randomised, phase 3 trial.

BACKGROUND: Renal-cell carcinoma is highly vascular, and proliferates primarily through dysregulation of the vascular endothelial growth factor (VEGF) pathway. We tested sunitinib and sorafenib, two oral anti-angiogenic agents that are effective in advanced renal-cell carcinoma, in patients with resected local disease at high risk for recurrence. METHODS: In this double-blind, placebo-controlled, randomised, phase 3 trial, we enrolled patients at 226 study centres in the USA and Canada. Eligible patients had pathological stage high-grade T1b or greater with completely resected non-metastatic renal-cell carcinoma and adequate cardiac, renal, and hepatic function. Patients were stratified by recurrence risk, histology, Eastern Cooperative Oncology Group (ECOG) performance status, and surgical approach, and computerised double-blind randomisation was done centrally with permuted blocks. Patients were randomly assigned (1:1:1) to receive 54 weeks of sunitinib 50 mg per day orally throughout the first 4 weeks of each 6 week cycle, sorafenib 400 mg twice per day orally throughout each cycle, or placebo. Placebo could be sunitinib placebo given continuously for 4 weeks of every 6 week cycle or sorafenib placebo given twice per day throughout the study. The primary objective was to compare disease-free survival between each experimental group and placebo in the intention-to-treat population. All treated patients with at least one follow-up assessment were included in the safety analysis. This trial is registered with ClinicalTrials.gov, number NCT00326898. FINDINGS: Between April 24, 2006, and Sept 1, 2010, 1943 patients from the National Clinical Trials Network were randomly assigned to sunitinib (n=647), sorafenib (n=649), or placebo (n=647). Following high rates of toxicity-related discontinuation after 1323 patients had enrolled (treatment discontinued by 193 [44%] of 438 patients on sunitinib, 199 [45%] of 441 patients on sorafenib), the starting dose of each drug was reduced and then individually titrated up to the original full doses. On Oct 16, 2014, because of low conditional power for the primary endpoint, the ECOG-ACRIN Data Safety Monitoring Committee recommended that blinded follow-up cease and the results be released. The primary analysis showed no significant differences in disease-free survival. Median disease-free survival was 5·8 years (IQR 1·6-8·2) for sunitinib (hazard ratio [HR] 1·02, 97·5% CI 0·85-1·23, p=0·8038), 6·1 years (IQR 1·7-not estimable [NE]) for sorafenib (HR 0·97, 97·5% CI 0·80-1·17, p=0·7184), and 6·6 years (IQR 1·5-NE) for placebo. The most common grade 3 or worse adverse events were hypertension (105 [17%] patients on sunitinib and 102 [16%] patients on sorafenib), hand-foot syndrome (94 [15%] patients on sunitinib and 208 [33%] patients on sorafenib), rash (15 [2%] patients on sunitinib and 95 [15%] patients on sorafenib), and fatigue 110 [18%] patients on sunitinib [corrected]. There were five deaths related to treatment or occurring within 30 days of the end of treatment; one patient receiving sorafenib died from infectious colitis while on treatment and four patients receiving sunitinib died, with one death due to each of neurological sequelae, sequelae of gastric perforation, pulmonary embolus, and disease progression. Revised dosing still resulted in high toxicity. INTERPRETATION: Adjuvant treatment with the VEGF receptor tyrosine kinase inhibitors sorafenib or sunitinib showed no survival benefit relative to placebo in a definitive phase 3 study. Furthermore, substantial treatment discontinuation occurred because of excessive toxicity, despite dose reductions. These results provide a strong rationale against the use of these drugs for high-risk kidney cancer in the adjuvant setting and suggest that the biology of cancer recurrence might be independent of angiogenesis. FUNDING: US National Cancer Institute and ECOG-ACRIN Cancer Research Group, Pfizer, and Bayer.

Novel management of pruritus in patients treated with IL-2 for metastatic renal cell carcinoma and malignant melanoma.

Pruritus has been a side effect, associated with several biologic response modifiers, most commonly interferons and interleukins. Reports of pruritus are anecdotal and have not been a focus of attention. Itch fibers are essentially pain fibers, and gabapentin is used for neuropathic pain. This has led to our formal investigation of gabapentin for interleukin-2 (IL-2)-related pruritus. Clinical records of 54 patients treated with high-dose IL-2 from January 2005 to December 2006 were reviewed. Among 30 patients, who complained of pruritus, 17 patients were given gabapentin. These 17 patients were interviewed using a specific IRB approved questionnaire, which quantified pruritus according to CTCAE v3.0 criteria. According to CTCAE scale, the mean pruritus before gabapentin was 2.41, which decreased to 0.65 after gabapentin treatment and was statistically significant (P<0.0005). IL-2 therapy is frequently associated with varying degrees of peripheral eosinophilia. Relationship between pruritus and the degree of eosinophilia was also analyzed. Patients grouped into mild eosinophilia (eosinophil count<1500/mL) and moderate to severe eosinophilia (eosinophil count>1500/mL) during HDIL-2 therapy was evaluated for pruritus. χ² test for independence of variable between degree of eosinophilia and pruritus was 0.714 with no statistically significant correlation. To summarize, gabapentin is used in our facility with excellent response against pruritus. Hypothesizing the likely mechanism of pruritus in patients treated with IL-2, we suggest that gabapentin should be considered an effective and safe treatment in IL-2-related pruritus, and this concept could be applied to pruritus encountered in similar clinical settings.

Safety and efficacy of sorafenib in elderly patients treated in the North American advanced renal cell carcinoma sorafenib expanded access program.

OBJECTIVE: In this retrospective analysis of the Advanced Renal Cell Carcinoma Sorafenib (ARCCS) program in North America, we compared the safety and efficacy of sorafenib in patients aged ≥70 with those aged <70 years. METHODS: Patients were treated with oral sorafenib twice daily until the occurrence of disease progression or treatment intolerance. The primary objective of the ARCCS program was making sorafenib available to patients with advanced renal cell carcinoma (RCC) in the USA and Canada before marketing approval was obtained; the secondary objective was the evaluation of its safety and efficacy. RESULTS: Of the 2,504 patients enrolled in the ARCCS program who received at least 1 dose of sorafenib, 736 (29%) were aged ≥70 years. The most common grade ≥3 adverse events included rash/desquamation (5% in both groups), hand-foot skin reaction (8% in those aged ≥70 years vs. 10% in those <70 years of age), hypertension (5 vs. 4%) and fatigue (7 vs. 4%). Partial response was seen in 4% of the patients in both age groups. The median overall survival for the ≥70-year versus <70-year groups was also similar (46 vs. 50 weeks). CONCLUSIONS: There were no substantial differences in safety and efficacy between patients aged ≥70 and <70 years with advanced RCC treated with sorafenib.

Safety and efficacy results of the advanced renal cell carcinoma sorafenib expanded access program in North America.

BACKGROUND: The Advanced Renal Cell Carcinoma Sorafenib (ARCCS) program made sorafenib available to patients with advanced renal cell carcinoma (RCC) before regulatory approval. METHODS: In this nonrandomized, open-label expanded access program, 2504 patients from the United States and Canada were treated with oral sorafenib 400 mg twice daily. Safety and efficacy were explored overall and in subgroups of patients including those with no prior therapy, nonclear cell (nonclear cell) RCC, brain metastases, prior bevacizumab treatment, and elderly patients. Sorafenib was approved for RCC 6 months after study initiation, at which time patients with no prior therapy or with nonclear cell RCC could enroll in an extension protocol for continued assessment for a period of 6 months. RESULTS: The most common grade > or =2 drug-related adverse events were hand-foot skin reaction (18%), rash (14%), hypertension (12%), and fatigue (11%). In the 1891 patients evaluable for response, complete response was observed in 1 patient, partial response in 67 patients (4%), and stable disease for at least 8 weeks in 1511 patients (80%). Median progression-free survival in the extension population was 36 weeks (95% confidence interval [CI], 33-45 weeks; censorship rate, 56%); median overall survival in the entire population was 50 weeks (95% CI, 46-52 weeks; censorship rate, 63%). The efficacy and safety results were similar across the subgroups. CONCLUSIONS: Sorafenib 400 mg twice daily demonstrated activity and a clinically acceptable toxicity profile in all patient subsets enrolled in the ARCCS expanded access program (clinicaltrials.gov identifier: NCT00111020).

Experience with sorafenib and the elderly patient.

Renal cell carcinoma primarily affects older individuals. Approximately half of all new renal cell carcinoma diagnoses are made in persons 65 years of age or older. Devising a treatment plan for the elderly patient population requires special consideration. Age-related physiological, cognitive, and social characteristics of elderly patients may influence each stage of patient care. Until recently, treatment options were limited for elderly patients with renal cell carcinoma. Sorafenib is the first multikinase inhibitor approved for use in renal cell carcinoma in the United States and Europe. In the phase III Treatment Approaches in Renal Cell Cancer Global Evaluation Trial, sorafenib significantly extended progression-free survival in patients with advanced renal cell carcinoma, regardless of age. Incidence rates of adverse events were not significantly higher in elderly patients receiving sorafenib than in younger patients. Thus, sorafenib represents an important treatment option for elderly patients with renal cell carcinoma. This report describes particular considerations for physicians to be aware of when choosing a treatment regimen for their elderly patients with renal cell carcinoma and offers recommendations on how to integrate specific management strategies into clinical practice that will optimize the use of sorafenib in the elderly. The strategies focus on patient selection, assessment of quality of life, management of adverse events, and appropriate dose modifications. The goal of these recommendations is to maximize the clinical benefit of sorafenib in the elderly patient population through appropriate use.

Phase II study of axitinib in sorafenib-refractory metastatic renal cell carcinoma.

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.

Therapeutic potential of curcumin in prostate cancer--V: Interference with the osteomimetic properties of hormone refractory C4-2B prostate cancer cells.

BACKGROUND: There is increasing evidence that the stringent selective pressure imposed by androgen ablation therapy on the residual prostate cancer cells may actually accelerate the development of the hormone refractory and bone metastatic phenotype. The propensity of prostate cancer to establish osseous metastases is very likely mediated by the osteomimetic properties of the prostate cancer cells. Prostate cancer cells acquire these "bone-like" properties in order to survive in the bony microenvironment. This process is facilitated by common growth factor trophisms between the bone stromal cells, osteoblasts, and the prostate cancer cells wherein a number of growth factors and their receptors are involved. Thus, a general inhibition of the tyrosine kinase signaling pathways may have a therapeutic advantage in interfering with the metastatic potential of these prostate cancer cells. This study focuses on the potential of curcumin, a plant based non-toxic tyrosine kinase inhibitor in interfering with the development of bone like properties of C4-2B, a highly metastatic derivative of LNCaP prostate cancer cell line. METHODS: C4-2B prostate cancer cells were analyzed for their constitutive expression and ligand inducible activation of growth factor receptors such as EGF-R and CSF1-R. Expression of bone-specific transcription factors such as Cbfa-1 and the production of PTHRP were followed. The ability of the C4-2B cells to mineralize under specific conditions was analyzed. The activation status of the transcription factor NF-kappa B was also followed. RESULTS: Curcumin inhibited the ligand-stimulated autophosphorylation of EGF-R and CSF1-R that were crucially involved in the development of osteomimetic properties of C4-2B cells. When C4-2B cells were grown under promineralization conditions, curcumin prevented the formation of the mineralized nodules. It also inhibited the expression of the core-binding factor a-1 in C4-2B cells which was responsible for the expression of several bone-specific proteins. The IKK activity was severely impaired, showing marked NF-kappa B inhibition. The experiments indicate that curcumin can also interfere with the development of the osteoblast and the osteoclast-like properties by these prostate cancer cells. CONCLUSIONS: The highly metastatic C4-2B prostate cancer cell line is already "programmed" to exhibit the bone-like properties that would at least in part explain its affinity to set up osseous metastases. Curcumin is able to interfere with the osteoblastic component as well as the osteoclastic component of this phenotype, by interfering with the growth factor receptor pathways and by inhibiting the NF-kappa B activation process. It is concluded that curcumin may inhibit the growth factor collaboration between the prostate cancer cells and the osteoblast/stromal cells, thus exhibiting a potential to prevent the establishment of bony metastases.

Mammalian target of rapamycin (mTOR) Inhibitors.

Current efforts in anticancer drug development are targeting key factors in cell-cycle regulation. Mammalian target of rapamycin (mTOR) is one such protein kinase that facilitates cell growth by stimulating the cell to traverse the G1 to S phase of the cell cycle. Rapamycin is the first defined inhibitor of mTOR, and the demonstration of its antitumor activity has led to great interest in this pathway as an antitumor mechanism. Analogues with better pharmacologic properties have been developed and have entered clinical trials. Human cell lines of renal cell cancer, among several other tumors, are sensitive to growth inhibition via this pathway. Ongoing clinical trials are evaluating renal cell cancer and other malignancies using therapy with mTOR inhibitors. These agents are more likely to induce growth inhibition rather than tumor regression.