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Simple Summary: Despite the increased risk of developing renal cell carcinoma (RCC) in patients with advanced chronic kidney disease (ACKD), little is known about the patient clinical characteristics and genetic mutations found in these RCC tumors. Using a multi-institutional research network, this study compiled clinical records and somatic tumor whole exome sequencing data of 296 adult patients with RCC, 61 of whom had ACKD. Patients with RCC and ACKD were more likely to be male, present with earlier stage RCC at diagnosis, and have lower rates of BAP1 mutations. Median overall survival was not reached in either group over a median follow-up of 31.3 months. These findings suggest RCC in patients with ACKD develops via a BAP1-independent mutational driver and further support BAP1 loss as a marker of disease aggressiveness. Background: Patients with advanced chronic kidney disease (ACKD) are at an increased risk of developing renal cell carcinoma (RCC), but molecular alterations in RCC specimens arising from ACKD and overall survival (OS) in affected patients are not well defined. Patients and Methods: Using the Oncology Research Information Exchange Network (ORIEN) Total Cancer Care® protocol, 296 consented adult patients with RCC and somatic tumor whole exome sequencing were included. Patients with ACKD were defined as those with serum creatinine ≥1.5 mg/dL prior to RCC diagnosis. Results: Of 296 patients with RCC, 61 met the criteria for ACKD. The most common somatic mutations in the overall cohort were in VHL (126, 42.6%), PBRM1 (102, 34.5%), and SETD2 (54, 18.2%). BAP1 had a decreased mutational frequency in RCC specimens from patients without ACKD as compared to those with ACKD (10.6% versus 1.6%), but this was not statistically significant in univariable (OR 0.14, p = 0.056) or multivariable (OR 0.15, p = 0.067) analysis. Median OS was not reached in either cohort. Conclusions: Using the clinicogenomic ORIEN database, our study found lower rates of BAP1 mutations in RCC specimens from patients with ACKD, which may reflect a BAP1-independent mutational driver of RCC in patients with ACKD. [ABSTRACT FROM AUTHOR]

The aim of this article is to review the current role of genomic testing in the risk, prognosis, and treatment of genitourinary malignancies. The authors selected guidelines, publications, and abstracts relevant to the current and emerging role of genomics in genitourinary cancers. The risk of developing genitourinary cancer can be stratified based on genomic data. Prostate cancer has the strongest degree of heritability, with BRCA1/2 and HOXB13 mutations playing a role in familial disease. Genomic data is on the verge of informing treatment decisions across genitourinary cancers. mCRPC has diverse genomic alterations that represent potential therapeutic targets, including alterations in the AR pathway, DNA damage and repair pathways, cell cycle pathways, PI3K pathway, and Wnt signaling. Genomic alterations in clear cell renal cell carcinoma can inform prognosis and mutations in mTOR pathways predict response to mTOR inhibitors. Urothelial carcinoma can be classified into different subtypes based on gene expression profiling, which provides prognostic information and predicts response to chemotherapy and immunotherapy. Specific mutations have been identified that predict response to therapy including ERCC2 mutations and cisplatin, DNA damage and repair mutations and checkpoint inhibitors, and FGFR3 mutations and FGFR tyrosine kinase inhibitors such as erdafitinib. Conclusion. Genitourinary malignancies have not felt the impact of genomic data as greatly as other cancer types. The majority of benefit lies in identifying patients at high risk of genitourinary cancer. Fortunately, breakthroughs are on the horizon that will result in a greater incorporation of genomic information into treatment decisions for patients with genitourinary cancer. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. Cancer 2011. © 2011 American Cancer Society. [ABSTRACT FROM AUTHOR]

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 &y& Elsevier]

PURPOSE: Biomarkers that predict response or toxicity to antiangiogenic therapy are sought to favorably inform the risk/benefit ratio. This study evaluated the association of vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGFR2) genetic polymorphisms with the development of hypertension (HTN) and clinical outcome in metastatic clear cell renal cell carcinoma (MCCRCC) patients treated with sunitinib. PATIENT AND METHODS: Sixty-three MCCRCC patients receiving sunitinib (50 mg 4/2) with available blood pressure (BP) data and germline DNA were retrospectively identified. A panel of candidate VEGF and VEGFR2 single nucleotide polymorphisms (SNPs) were evaluated for associations with the development of hypertension and clinical outcome. RESULTS: VEGF SNP −634 genotype was associated with the prevalence and duration of sunitinib-induced hypertension (as defined by systolic pressure ≥150 mmHg and/or diastolic pressure ≥90 mmHg) in both univariable analysis ( P = .03 and .01, respectively) and multivariable analysis, which adjusted for baseline BP and use of antihypertension medication ( P = .05 and .02, respectively). Patients with the GG genotype were estimated to have a greater likelihood of being hypertensive during treatment compared with patients with the CC genotype (odds ratio of 13.62, 95% confidence interval [CI] 3.71-50.04). No single VEGF or VEGFR SNPs were found to correlate with clinical outcome. However, the combination of VEGF SNP 936 and VEGFR2 SNP 889 were associated with overall survival after adjustment for prognostic risk group ( P = .03). CONCLUSIONS: In MCCRCC patients treated with sunitinib, VEGF SNP −634 is associated with hypertension and a combination of VEGF SNP 936 and VEGFR2 SNP 889 genotypes is associated with overall survival. Cancer 2012;. © 2011 American Cancer Society. [ABSTRACT FROM AUTHOR]

Study Type - Therapy (individual cohort) Level of Evidence 2b 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/m2/day and IFN-α 5.0 mU/m2/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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

OBJECTIVE Low-dose interleukin-2 (IL-2) is a historical treatment for metastatic renal cell carcinoma (mRCC). Increased vascular endothelial growth factor (VEGF) levels inhibit dendritic cell (DC) differentiation and augment production of immunosuppressive regulatory T (Treg) cells. Bevacizumab is an antibody that binds to VEGF, has activity in mRCC and may augment the anti-tumour immune effects of IL-2. To determine the clinical and immunomodulatory effects of this combination, a prospective, phase II trial of bevacizumab plus low-dose IL-2 was conducted. PATIENTS AND METHODS Patients with untreated mRCC received bevacizumab (10 mg/kg i.v. every 2 weeks) and IL-2 (125 000 units/kg/day subcutaneously from Monday to Friday for 6 consecutive weeks followed by a 2-week rest period). Endpoints included progression-free survival, Response Evaluation Criteria in Solid Tumors-defined objective response rate, immunomodulatory effects and safety. RESULTS Between January 2005 and September 2007, twenty-six patients with untreated mRCC were enrolled. The median progression-free survival was 9.6 months (95% CI, 4.1-16.9 months) The objective response rate was 15% and an additional 38% of patients had tumour burden reduction of < 30%. Grade 3 constitutional adverse events (fatigue, fever/ chills) and neutropenia were observed in 42% and 12% of patients, respectively. Peripheral blood CD1c + myeloid and CD303 + plasmacytoid DC increased during treatment as did IL-8 levels and CD4 + CD25 + FoxP3 + Treg cells. No changes in T helper type 1/2- associated cytokines were observed. CONCLUSION Bevacizumab plus low-dose IL-2 has modest clinical activity in mRCC. Toxicity was largely IL-2 related without enhancement of bevacizumab-related toxicity. Biological data indicate inhibition of VEGF levels and increase of immunosuppressive Treg cells without an effect on DC activation. [ABSTRACT FROM AUTHOR]

Purpose: Metastasectomy is often incorporated in overall treatment in patients with metastatic renal cell carcinoma. While this approach was studied in the immunotherapy era, only a few cases have been described in the targeted therapy era. Thus, we evaluated the role of metastasectomy in patients with metastatic renal cell carcinoma who received prior targeted therapy. Materials and Methods: We retrospectively evaluated the records of patients who underwent consolidative metastasectomy after targeted therapy at 3 institutions from 2004 to 2009. All patients received at least 1 cycle of targeted therapy before surgical resection of all visible disease. Results: We identified 22 patients. Metastasectomy sites included the retroperitoneum in 12 patients, lung in 6, adrenal gland in 2, bowel in 2, and mediastinum, bone, brain and inferior venal caval thrombus in 1 each. A total of 6 postoperative complications were observed in 4 patients within 12 weeks after surgery, which resolved with appropriate management. Postoperatively 9 patients received at least 1 targeted therapy. In 11 patients recurrence developed a median of 42 weeks after metastasectomy and another 11 experienced no recurrence at a median of 43 weeks. At a median followup of 109 weeks 21 patients were alive and 1 died of renal cell carcinoma 105 weeks after metastasectomy. Conclusions: In a cohort of select patients with a limited tumor burden after treatment with targeted agents consolidative metastasectomy is feasible with acceptable morbidity. Significant time off targeted therapy and long-term tumor-free status are possible with this approach. [ABSTRACT FROM AUTHOR]

The article provides information on a study which investigated the safety and activity of sorafenib in bevacizumab- or sunitinib-refractory metastatic renal cell carcinoma (mRCC) patients. Background on vascular endothelial growth factor (VEGF)-targeted agents is offered. Outcome measures included tumor burden reduction rate, progression-free survival (PFS), duration of response, overall survival and safety. A discussion on the research findings is detailed. It observes that sorafenib is safe and possible in patients with mRCC refractory to either drugs.

Advances in the understanding of the biology of renal cell carcinoma have led to recent approval of several new agents including drugs that target vascular endothelial growth factor. Sunitinib is an oral tyrosine kinase inhibitor which interferes with multiple intracellular tumorogenic pathways, and has demonstrated impressive antitumor activity in phase II and subsequently improvement in progression free survival in phase III renal cancer trials. We review the unique side effects of sunitinibtherapy with emphasis on establishing effective patient education for anticipation and early management of therapy-related side effects. [ABSTRACT FROM AUTHOR]

Study Type - Therapy (case series) Level of Evidence 4 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. [ABSTRACT FROM AUTHOR]

Purpose: We assessed the activity of neoadjuvant sunitinib on primary renal tumors in patients with advanced renal cell carcinoma as well as the feasibility and safety of subsequent surgical resection. Methods: A total of 19 patients with advanced renal cell carcinoma deemed unsuitable for initial nephrectomy due to locally advanced disease or extensive metastatic burden were treated with 50 mg sunitinib daily for 4 weeks on followed by 2 weeks off. Tumor response was assessed by Response Evaluation Criteria in Solid Tumors every 2 cycles and the rate of conversion to resectable status was estimated. Results: Median patient age was 64 years and initial median radiographic renal tumor size was 10.5 cm. Clinical stage was N+ (10) and M+ (15). No patients experienced a complete response. Partial responses of the primary tumor were noted in 3 patients (16%), 7 (37%) had stable disease and 9 (47%) had disease progression in the primary tumor. Overall tumor response included 2 patients (11%) with partial response, 7 (37%) with stable disease and 10 (53%) with disease progression. At a median followup of 6 months (range 1 to 15) 4 patients (21%) had undergone nephrectomy and 5 died of disease progression. No unexpected surgical morbidity was encountered. Viable tumor was present in all 4 specimens. Sunitinib was associated with grade 3–4 toxicity in 7 patients (37%) and treatment was discontinued in 1 due to toxicity. Conclusions: Administration of sunitinib in patients with advanced renal cell carcinoma with the primary tumor in place is feasible and can lead to a reduction in tumor burden that can facilitate subsequent surgical resection. [Copyright &y& Elsevier]

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. [ABSTRACT FROM AUTHOR]

Pegylated interferon α-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 α-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). 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 μg/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/m2 SC), and 5.0 MIU/m2 SC TIW was administered during weeks 2, 3, 5 and 6. 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. The combination of PEG-Interferon and SC rIL-2 can be administered with acceptable toxicity. [ABSTRACT FROM AUTHOR]

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. [Copyright &y& Elsevier]

The article discusses the systemic management options and the second-line therapy for patients with metastatic bladder cancer. Advanced bladder cancer is the most depressing genitourinary neoplasm in the management of advanced renal cell carcinoma. Furthermore, variety of molecular pathways that are amenable to treatment with current agents including overexpression of epidermal growth factor receptor and vascular endothelial growth factor greatly influences bladder cancer.

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. [ABSTRACT FROM AUTHOR]

Abstract: Background: Capecitabine is an orally administered fluoropyrimidine that is converted to 5-fluorouracil by thymidine phosphorylase. In view of the recognized synergism of fluoropyrimidines with interferon-α (IFNα), a Phase II study to characterize the toxicity and efficacy of the combination of capecitabine and rHuIFNα-2a for the treatment of patients with renal cell carcinoma (RCC) was conducted. Patients and Methods: Eligible patients had metastatic RCC, measurable disease, and no prior systemic therapy. A total of 32 patients were entered into the study. Histologic subtypes included clear cell (n = 28) and nonclear cell (n = 2). Histology was unknown for 2 patients. The first 14 patients were treated with capecitabine 1,000 mg/m2 twice daily on days 1–14 and 22–36, combined with IFNα-2a 3.0 MU/m2 subcutaneously 3 times weekly. Because of toxicity requiring dose reductions during the first cycle, the capecitabine dose was reduced to 825 mg/m2 twice daily on days 1–14 and 22–36 in the subsequent 18 patients. Results: Responses were seen in 4 of 32 patients (12%) (95% confidence interval 4% to 29%), with 1 complete response and 3 partial responses. There were 3 responses that occurred at the higher capecitabine starting dose level. Median response duration was 12 months (range 4.6–15.0). There were 12 patients (38%) who had stable disease for at least 2 cycles (duration 2.9 to 33.6+ months). One-year survival was 63%. Toxicity was moderate to severe and required dose reductions in 88% of patients. There were 23 patients who had grade ≥3 toxicity. Conclusion: The combination of capecitabine and IFNα-2a has limited activity in metastatic RCC and is associated with moderate-to-severe toxicity. [Copyright &y& Elsevier]