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Introduction: Sarcomatoid renal cancer (sRCC) patients have poor outcomes. EA1808 evaluated sunitinib and gemcitabine (SG) and sunitinib alone (S) in sRCC in a randomized cooperative group phase II trial (NCT01164228)., Patients and Methods: Pts were aggregated 1:1 to SG (45 pts) or S (40 pts) using a 2-stage design. sRCC pts with ≤ 1 prior nonvascular endothelial growth factor tyrosine kinase inhibitor were stratified into prognostic groups: good (clear cell, < 20% sarcomatoid, PS 0), intermediate (20%-50% sarcomatoid, PS 0), and poor (nonclear cell or > 50% sarcomatoid or PS 1). The primary endpoint was response rate (RR). For SG, the null RR was 15% and a 30% RR was of interest. For S, a 20% RR was of interest vs. a 5% null rate. Secondary endpoints were progression-free survival, overall survival, and safety., Results: Both arms met protocol criteria for stage 2 of accrual. A total of 47 pts were randomized to SG and 40 to S. The SG arm had 9 of 45 evaluable patient responses (RR of 20%; CI = [13%-31%]) not meeting the predetermined threshold for success. The sunitinib arm met its endpoint with 6/37 (RR of 16%; CI = [9%-27%]) evaluable responses. Grade ≥ 3 events were experienced by 36 in the SG arm and 17 in the sunitinib arm CONCLUSIONS: EA1808 was the largest and first randomized cytotoxic trial for sarcomatoid RCC. Sunitinib alone but not the SG met the preset threshold of success. Cytotoxic chemotherapy is only useful in limited clinical scenarios for sRCC., Competing Interests: Disclosure No authors have a conflict of interest pertaining to the content of this manuscript., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: The role and sequencing of combination immuno-oncology (IO) therapy following progression on or after first-line IO therapy has not been well-established. The Fast Real-time Assessment of Combination Therapies in Immuno-ONcology (FRACTION) program is an open-label, phase 2 platform trial designed to evaluate multiple IO combinations in patients with advanced renal cell carcinoma (aRCC) who progressed during or after prior IO therapy. Here, we describe the results for patients treated with nivolumab plus ipilimumab. For enrollment in track 2 (reported here), patients with histologically confirmed clear cell aRCC, Karnofsky performance status ≥70%, and life expectancy ≥3 months who had previously progressed after IO (anti-programmed death 1 (PD-1), anti-programmed death-ligand 1 (PD-L1), or anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4)) therapy were eligible. Previous treatment with anti-CTLA-4 therapy plus anti-PD-1/PD-L1 therapy precluded eligibility for enrollment in the nivolumab plus ipilimumab arm. Patients were treated with nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for four doses, followed by nivolumab 480 mg every 4 weeks for up to 2 years or until progression, toxicity, or protocol-specified discontinuation. The primary outcome measures were objective response rate (ORR), duration of response (DOR), and progression-free survival (PFS) rate at 24 weeks. Secondary outcomes were safety and tolerability up to 2 years. Overall survival (OS) was a tertiary/exploratory endpoint. Overall, 46 patients were included with a median follow-up of 33.8 months. The ORR was 17.4% (95% CI, 7.8 to 31.4) with eight (17.4%) patients achieving partial response. Stable disease was achieved in 19 (41.3%) patients, while 14 (30.4%) had progressive disease. Median DOR (range) was 16.4 (2.1+ to 27.0+) months. The PFS rate at 24 weeks was 43.2%, and median OS was 23.8 (95% CI, 13.2 to not reached) months. Grade 3-4 immune-mediated adverse events were reported in seven (15.2%) patients. No treatment-related deaths were reported. Patients with aRCC treated with nivolumab plus ipilimumab may derive durable clinical benefit after progression on previous IO therapies, including heavily pretreated patients, with a manageable safety profile that was consistent with previously published safety outcomes. These outcomes contribute to the knowledge of optimal sequencing of IO therapies for patients with aRCC with high unmet needs., Trial Registration Number: NCT02996110., Competing Interests: Competing interests: TKC reports consulting or advisory board fees, honoraria, and research grants from AstraZeneca, Aravive, AVEO Pharmaceuticals, Bayer, Bristol Myers Squibb (BMS), Calithera, Circle Pharma, Eisai, EMD Serono, Exelixis, GlaxoSmithKline, IQVIA, Infinity, Ipsen, Janssen, Kanaph, Lilly, Merck, NiKang, Nuscan, Novartis, Pfizer, Roche, Sanofi/Aventis, Surface Oncology, Takeda, Tempest, Up-To-Date, and CME events (Peerview, OncLive, MJH and others), outside the submitted work. Institutional patents filed on molecular mutations and immunotherapy response/toxicity, and circulating tumor DNA. Equity holdings: Tempest, Pionyr, Osel, and Precede Bio. Committees: NCCN, GU Steering Committee, ASCO/ESMO, ACCRU, and KidneyCan. Medical writing and editorial assistance support may have been funded by communications companies in part. Mentored several non-US citizens on research projects with potential funding (in part) from non-US sources/foreign components. The institution (Dana-Farber Cancer Institute) may have received additional independent funding of drug companies or/and royalties potentially involved in research around the subject matter. Dr Choueiri is supported in part by the Dana-Farber/Harvard Cancer Center Kidney SPORE and Program, the Kohlberg Chair at Harvard Medical School and the Trust Family, Michael Brigham, Pan-Mass Challenge, and Loker Pinard Funds for Kidney Cancer Research at DFCI. CV provided upon request for scope of clinical practice and research. HK reports institutional research grant funding from Apexigen, BMS, and Merck; personal fees from Array Biopharma, BMS, Calithera Biosciences, Celldex, ChemoCentryx, Clinigen, Elevate Bio, GI reviewers, GigaGen, Immunocore, Instil Bio, Iovance, Merck, Shionogi, and Signatera. SG reports consulting or advisory role from BMS, Bayer, Pfizer, Exelixis, Corvus Pharmaceuticals, Sanofi/Genzyme, EMD Serono, Seattle Genetics/Astellas, Eisai, Merck, AVEO Pharmaceuticals, and QED Therapeutics; and research funding (institutional) from Pfizer, Merck, Agensys, Novartis, BMS, Bayer, Eisai, Seattle Genetics/Astellas, Calithera Biosciences, Immunomedics, Corvus Pharmaceuticals, and Surface Oncology. SST reports consulting or advisory board fees from Merck, Intellisphere LLC, Natera, BMS, and Exelixis; patent pending (Fred Hutchinson Cancer Center); and research funding (institutional) from Genentech, BMS, Merck Sharp & Dohme, Calithera Biosciences, Pfizer, Jounce Therapeutics, Nektar, Exelixis, and Clinigen Group. TMK has nothing to disclose. RP reports consulting fees from Karyopharm Therapeutics and BiolineRx. SN has nothing to disclose. GP reports advisory board fees from AstraZeneca, BMS, Ipsen, Janssen, Merck Sharp & Dohme, Novartis, and Pfizer. MAC reports consulting or advisory fees from Astellas Pharma, AbbVie, Roche/Genentech, Pfizer, and Foundation Medicine; and research funding (institutional) from BMS, AstraZeneca, Pfizer, and Gilead Science. VC reports consulting or speakers’ bureau fees from Ipsen, Eisai, Merck, AstraZeneca, Pfizer, Novartis, BMS, Astellas and Janssen. EF has nothing to disclose. C-HL reports research funding (institutional) from BMS, Calithera Biosciences, Eisai, Eli Lilly, Exelixis, Merck, and Pfizer; consulting fees from Amgen, BMS, Exelixis, Eisai, Merck, Pfizer, and EMD Serono; and honoraria from AiCME, Intellisphere, and Research to Practice. SJH reports compensation for advisory boards and speakers’ bureaus from Astellas, AstraZeneca, Bayer, BMS, Eisai, Exelixis, Janssen, Ipsen, Merck, Roche, Sanofi, Seagen, and SignalChem; institutional research or grant funding from Astellas, AstraZeneca, Ayala, Bayer, BMS, Eisai, Exelixis, Janssen, Ipsen, Merck, Roche, Sanofi, Seagen, and SignalChem. WHM reports consulting or advisory board fees from BMS, Merck, Roche, Novartis, GlaxoSmithKline, and Amgen; honoraria from BMS, Roche, Novartis, and GlaxoSmithKline; and research funding (institutional) from Merck, BMS, Novartis, GlaxoSmithKline, Roche, AstraZeneca, MethylGene, and MedIm. SSS, C-WL, HD, and PB are employed by and has stock ownership in BMS. RJM reports advisory board fees from AstraZeneca, AVEO Pharmaceuticals, Eisai, EMD Serono, Exelixis, Genentech/Roche, Incyte, Lilly Oncology, Merck, Novartis, and Pfizer; and research funding (institutional) from BMS, Eisai, Exelixis, Genentech/Roche, Merck, and Pfizer. BE reports research funding (institutional) from BMS; consulting fees from Pfizer, BMS, Ipsen, AVEO Pharmaceuticals, Oncorena, and Eisai; honoraria from Pfizer, BMS, Ipsen, Oncorena, and Eisai; and travel accommodations and expenses from BMS, Ipsen, and Merck Sharp & Dohme., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Non-clear cell renal cell carcinoma (nccRCC) accounts for ≤20% of RCC cases. Lenvatinib (a multitargeted tyrosine kinase inhibitor) in combination with everolimus (an mTOR inhibitor) is approved for the treatment of advanced RCC after one prior antiangiogenic therapy., Objective: To determine the safety and efficacy of lenvatinib plus everolimus as a first-line treatment for patients with advanced nccRCC., Design, Setting, and Participants: This open-label, single-arm, multicenter, phase 2 study enrolled patients with unresectable advanced or metastatic nccRCC and no prior anticancer therapy for advanced disease., Intervention: Lenvatinib (18 mg) plus everolimus (5 mg) orally once daily., Outcome Measurements and Statistical Analysis: The primary endpoint was the objective response rate (ORR) as assessed by investigators according to Response Evaluation Criteria in Solid Tumors version 1.1. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety assessments. The 95% confidence intervals (CIs) for ORRs were calculated using the two-sided Clopper-Pearson method. Median PFS and median OS were estimated using the Kaplan-Meier product-limit method and their 95% CIs were estimated via a generalized Brookmeyer and Crowley method., Results and Limitations: The study (start date: February 20, 2017) enrolled 31 patients with nccRCC (papillary, n = 20; chromophobe, n = 9; unclassified, n = 2). At the data cutoff date (July 17, 2019), the best overall response was a partial response (eight patients: papillary, n = 3; chromophobe, n = 4; unclassified, n = 1) for an overall ORR of 26% (95% CI 12-45). Median PFS was 9.2 mo (95% CI 5.5-not estimable), and median OS was 15.6 mo (95% CI 9.2-not estimable). The most common treatment-emergent adverse events were fatigue (71%), diarrhea (58%), decreased appetite (55%), nausea (55%), and vomiting (52%). Limitations include the small sample size and single-arm design., Conclusions: Lenvatinib plus everolimus showed promising anticancer activity in patients with advanced nccRCC with an ORR of 26% and is worthy of further study. The safety profile was consistent with the established profile of the study-drug combination., Patient Summary: We examined the combination of lenvatinib plus everolimus as the first therapy for 31 patients who had advanced nccRCC. We found that this treatment seemed effective, because most patients had a decrease in tumor size and manageable treatment-related side effects., Clinical Registration: This trial is registered at ClinicalTrials.Gov as NCT02915783., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Importance: Response patterns with immunotherapy may differ from those of other treatments. This warrants further investigation because some patients may benefit from continued immunotherapy beyond Response Evaluation Criteria in Solid Tumors (RECIST)-defined first progression., Objective: To evaluate the safety and potential benefit of treatment with nivolumab, a programmed cell death 1 immune checkpoint inhibitor, beyond investigator-assessed first progression in patients with metastatic renal cell carcinoma (mRCC)., Design, Setting, and Participants: Subgroup analysis of a blinded, randomized, multicenter, phase 2 dose-ranging trial initiated May 31, 2011, including patients with clear-cell mRCC previously treated with antiangiogenic therapy. Data cutoffs for this subgroup analysis were May 15, 2013, for progression-free survival and objective response rate and March 5, 2014, for overall survival and duration of response. In this analysis, patients treated beyond first progression received their last dose of nivolumab more than 6 weeks after RECIST-defined progression, and patients not treated beyond first progression discontinued nivolumab before or at RECIST-defined progression., Interventions: Nivolumab 0.3, 2, or 10 mg/kg intravenously every 3 weeks., Main Outcomes and Measures: Safety and efficacy of nivolumab treatment., Results: Of 168 patients (median [range] age, 61 [37-81] years; 72% male) randomized to nivolumab, 154 experienced progression (36 were treated beyond first progression, 26 were treated beyond first progression for ≤6 weeks, and 92 were not treated beyond first progression), 13 were treated and did not experience progression, and 1 was not treated. Prior to first progression, the RECIST-defined objective response rate was 14% (5 patients) and 16% (15 patients), and median progression-free survival was 4.2 (95% CI, 2.8-5.5) and 2.6 (95% CI, 1.5-3.9) months in patients treated and not treated beyond progression, respectively. Following initial progression, 25 (69%) patients treated beyond progression experienced subsequent tumor reduction or stabilization in target lesion size. The incidence of treatment-related adverse events was higher in patients treated beyond progression (n = 29 [81%]) vs those not treated beyond progression (n = 61 [66%]); however, after adjusting for length of treatment exposure, incidence was lower in patients treated beyond progression (322.9 vs 518.7 incidence rate/100 patient-years for patients treated vs not treated beyond progression)., Conclusions and Relevance: In this subgroup analysis, a proportion of patients who continued treatment beyond RECIST-defined first progression demonstrated sustained reductions in tumor burden or stabilization in the size of target lesions, with an acceptable safety profile. Further analysis will help define the clinical benefit for patients with mRCC treated with nivolumab beyond progression., Trial Registration: clinicaltrials.gov Identifier: NCT01354431.

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., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Purpose: Nivolumab is a fully human immunoglobulin G4 programmed death-1 immune checkpoint inhibitor antibody that restores T-cell immune activity. This phase II trial assessed the antitumor activity, dose-response relationship, and safety of nivolumab in patients with metastatic renal cell carcinoma (mRCC)., Patients and Methods: Patients with clear-cell mRCC previously treated with agents targeting the vascular endothelial growth factor pathway were randomly assigned (blinded ratio of 1:1:1) to nivolumab 0.3, 2, or 10 mg/kg intravenously once every 3 weeks. The primary objective was to evaluate the dose-response relationship as measured by progression-free survival (PFS); secondary end points included objective response rate (ORR), overall survival (OS), and safety., Results: A total of 168 patients were randomly assigned to the nivolumab 0.3- (n = 60), 2- (n = 54), and 10-mg/kg (n = 54) cohorts. One hundred eighteen patients (70%) had received more than one prior systemic regimen. Median PFS was 2.7, 4.0, and 4.2 months, respectively (P = .9). Respective ORRs were 20%, 22%, and 20%. Median OS was 18.2 months (80% CI, 16.2 to 24.0 months), 25.5 months (80% CI, 19.8 to 28.8 months), and 24.7 months (80% CI, 15.3 to 26.0 months), respectively. The most common treatment-related adverse event (AE) was fatigue (24%, 22%, and 35%, respectively). Nineteen patients (11%) experienced grade 3 to 4 treatment-related AEs., Conclusion: Nivolumab demonstrated antitumor activity with a manageable safety profile across the three doses studied in mRCC. No dose-response relationship was detected as measured by PFS. These efficacy and safety results in mRCC support study in the phase III setting., (© 2014 by American Society of Clinical Oncology.)

The NCCN Guidelines for Kidney Cancer provide multidisciplinary recommendations for the clinical management of patients with clear cell and non-clear cell renal carcinoma. These NCCN Guidelines Insights highlight the recent updates/changes in these guidelines, and updates include axitinib as first-line treatment option for patients with clear cell renal carcinoma, new data to support pazopanib as subsequent therapy for patients with clear cell carcinoma after first-line treatment with another tyrosine kinase inhibitor, and guidelines for follow-up of patients with renal cell carcinoma., (Copyright © 2015 by the National Comprehensive Cancer Network.)

Although tyrosine kinase inhibitors (TKI) are the most common first-line therapy for metastatic renal cell carcinoma, high-dose interleukin-2 (HD-IL2) remains the only agent that provides durable complete responses. The optimal sequence of these agents remains uncertain. This retrospective multi-institutional study examined the safety and efficacy of HD-IL2 following TKI therapy. After IRB approval at 7 HD-IL2 centers, data relating to patient, disease, and treatment characteristics among 40 consecutive patients with metastatic renal cell carcinoma who were treated with HD-IL2 after at least 1 prior TKI therapy were retrospectively collected. The most common cardiac adverse events were grade 3 hypotension and vascular leak syndrome. Six patients (15%) experienced other grade ≥3 cardiac adverse events. There were 2 treatment-related deaths due to congestive heart failure, occurring in 1 patient with short TKI to HD-IL2 interval and another patient with an abnormal baseline cardiac stress test. Best responses included 2 CRs (5%, duration 40+ and 62+ mo), 3 PRs (8%, duration 6, 11, and 24 mo), 13 SD (32%, median duration 12 mo), 20 PD (50%), and 2 not evaluable patients. Median overall survival was 22 months. Administration of HD-IL2 could be safe and effective after TKI therapy; however, careful selection of patients is critical. We recommend baseline cardiac risk factor assessment, screening with both cardiac stress test and echocardiogram, and allowing a TKI to HD-IL2 interval of at least 2 months.

High-dose (HD) IL-2 is approved to treat renal cell carcinoma (RCC) with modest response rates and significant toxicity. Enhancement of cytotoxic T-cell activity by IL-2 is 1 mechanism of action. IL-2 also stimulates regulatory T lymphocytes (Tregs), which are associated with poor prognosis. Favorable outcomes are associated with greater rebound absolute lymphocyte count (Fumagalli 2003). DD depletes IL-2 receptor (CD25 component) expressing cells. We hypothesized that sequential therapy could complement each other; DD would deplete Tregs so IL-2 could more effectively stimulate proliferation and activity of cytotoxic T lymphocytes. Patients (n=18) received standard HD IL-2 and 1 dose of DD daily for 3 days; periodic flow cytometry and complete blood counts were performed. Group A included 3 patients to assess safety only with DD 6 μg/kg between the IL-2 courses. Group B included 9 patients at 9 μg/kg DD before the IL-2 courses. Group C included 6 patients at 9 μg/kg DD between the IL-2 courses. Efficacy using the RECIST criteria was assessed after the treatment. Fifteen patients from a study of IL-2 without DD served as controls for toxicity comparison and 13 of these for flow cytometry comparisons. No unusual toxicity was noted. For group B/C patients receiving DD, the median decline in Tregs was 56.3% from pre-DD to post-DD (P=0.013). Peak absolute lymphocyte count change from baseline was +9980/μL for group B, +4470/μL for group C, and +4720/μL for the controls (P=0.005 B vs. C). The overall response rate was 5 of 15 (33%); 3 of 9 (33%) and 2 of 6 (33%) for groups B and C, respectively, including 2 patients with sarcomatoid RCC and 1 with earlier sunitinib therapy.

The development and validation of measures that provide disease-specific, patient-reported outcomes have become increasingly relevant in the care of cancer patients, especially for assessing symptoms from the patient's perspective. Recently, two patient symptom questionnaires were developed for kidney cancer patients, the Renal Cell Carcinoma-Symptom Index (RCC-SI) and the Functional Assessment of Cancer Therapy-Kidney Symptom Index (FKSI). This article describes the development of the revised FKSI scale (FKSI-19) and reconciles its use with the RCC-SI. Fifty participants with advanced kidney cancer commented on their symptoms and concerns about kidney cancer and this input was used to revise FKSI items. These patients also completed the RCC-SI, the Functional Assessment of Cancer Therapy-General (FACT-G), and an older version of the FKSI scale. We qualitatively reviewed item wording and content coverage across the two instruments, examined correlations between the scales, and calculated basic psychometrics on each scale. We found that the FKSI-19 and the RCC-SI addressed similar symptoms. Qualitative and descriptive statistical analyses demonstrated considerable overlap between the two instruments (rho=0.88, P<0.001). Cronbach's alpha for the FKSI-19 and RCC-SI were both good, at 0.86 and 0.92, respectively. The FKSI-19 has some advantages over the RCC-SI. The FKSI-19 has more clarity in item phrasing, is shorter in length, and covers a similar breadth of disease-based symptoms when compared to the RCC-SI.

The development of molecular therapeutic agents has revolutionized the treatment of metastatic renal cell carcinoma, but the long-term complications of these novel medications are not yet well-defined. We report the case of a 61-year-old woman who presented with metastatic renal cell carcinoma to the liver and contralateral kidney and renal pelvis 6 years after nephrectomy. Treatment with four cycles of sunitinib malate resulted in an initial near-complete radiographic response. Subsequently, the patient presented with flank pain, acute renal failure, and hydronephrosis of her solitary kidney during her fourth cycle of treatment. A temporizing percutaneous nephrostomy tube was placed, and antegrade contrast studies showed a filling defect and complete distal ureteral occlusion. Ureteroscopy revealed ureteral obstruction by a soft-tissue mass. Pathologic examination demonstrated necrotic renal cell carcinoma, presumably due to sloughing of the previously identified renal pelvic metastasis. We discuss the implications of this unusual complication of complete ureteral obstruction from necrotic tumor in a patient with a near-complete response to sunitinib.

Purpose: To compare the effect of high-dose interleukin-2 (HD IL-2) vs other cytokine therapies on 1-, 2, and 5-yr overall survival in patients with metastatic renal cell cancer (RCC)., Patients and Methods: We conducted a retrospective chart review of patients with untreated metastatic RCC treated by a single investigator. The different treatment groups included HD IL-2, low-dose IL-2 alone or in combination, interferon alpha alone and other therapies. The primary end point was survival from time of treatment., Results: A total of 85 patients were studies with a median follow up of 13 mo (0.6-112.9). Median age at treatment was 59 yr with predominantly male patients and histology of clear cell type. Thirty-four percent received HD IL-2 and treatment was initiated less than 6 mo from the time of diagnosis in 66%. For all patients, median survival was 16 mo with a 5-yr survival of 12%. Two factors were good predictors of overall survival: Karnofsky performance status (KPS) of 100 (p < 0.0001) and soft tissue metastasis (p = 0.01). When comparing HD IL-2 to all other groups, median survival was 18 vs 14 mo and 1-yr survival was 74% vs 51%, respectively., Conclusion: HD IL-2 is associated with clinically meaningful improvement in median and 1-yr survival.

Purpose of Review: Highlighted in this review are the important preclinical and clinical updates of interleukin (IL)-2-based cancer immunotherapy that have been published during the last year., Recent Findings: The review starts with a summary of the preclinical breakthroughs involving IL-2. The authors briefly examine two recent studies that take very different approaches to overcome the toxicities associated with IL-2 therapy. The first involves IL-2 gene transduction into tumor-infiltrating lymphocytes, and the latter discusses the use of a superoxide dismutase mimetic to ameliorate the hypotensive effects of IL-2. This is followed by a discussion of the key roles that T regulatory cells and transforming growth factor-beta have in immunosuppression, and how they interplay with IL-2. Next they review the clinical updates of IL-2 in melanoma, including IL-2 as adjuvant therapy, IL-2-based biochemotherapy, and intralesional IL-2 for soft-tissue metastases. Finally, the authors point out the recent clinical developments of IL-2 in renal cell carcinoma, including high-dose IL-2 as adjuvant therapy, and then focus on its role in the management of metastatic disease., Summary: IL-2 remains a valuable treatment option for patients with metastatic melanoma or renal cell carcinoma. Some of the recent updates in IL-2 therapy address important questions regarding the use of this drug, and others generate equally important hypotheses that could lead to better clinical outcomes in the future.