Publications by authors named "M Dror Michaelson"

170 Publications

Dana-Farber Cancer Institute/Mass General Brigham Fellowship Response to the COVID-19 Pandemic.

JCO Oncol Pract 2021 Feb 2:OP2000894. Epub 2021 Feb 2.

Division of Hematology and Oncology, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA.

The coronavirus disease (COVID)-19 pandemic has affected graduate medical education training programs, including hematology-oncology fellowship programs, both across the United States and abroad. Within the Dana-Farber Cancer Institute/Mass General Brigham hematology-oncology fellowship program, fellowship leadership had to quickly reorganize the program's clinical, educational, and research structure to minimize the risk of COVID-19 spread to our patients and staff, allow fellows to assist in the care of patients with COVID-19, maintain formal didactics despite physical distancing, and ensure the mental and physical well-being of fellows. Following the first wave of patients with COVID-19, we anonymously surveyed the Dana-Farber Cancer Institute/Mass General Brigham first-year fellows to explore their perceptions regarding what the program did well and what could have been improved in the COVID-19 response. In this article, we present the feedback from our fellows and the lessons we learned as a program from this feedback. To our knowledge, this represents the first effort in the hematology-oncology literature to directly assess a hematology-oncology program's overall response to COVID-19 through direct feedback from fellows.
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http://dx.doi.org/10.1200/OP.20.00894DOI Listing
February 2021

Correlative serum biomarker analyses in the phase 2 trial of lenvatinib-plus-everolimus in patients with metastatic renal cell carcinoma.

Br J Cancer 2021 Jan 7;124(1):237-246. Epub 2020 Oct 7.

Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Background: No biomarkers have been established to predict treatment efficacy in renal cell carcinoma (RCC). In an exploratory retrospective analysis of a Phase 2 study, we constructed composite biomarker scores (CBSs) to predict progression-free survival (PFS) and overall survival (OS) in patients with metastatic RCC randomised to receive lenvatinib-plus-everolimus.

Methods: Of 40 biomarkers tested, the 5 most strongly associated with PFS (HGF, MIG, IL-18BP, IL-18, ANG-2) or OS (TIMP-1, M-CSF, IL-18BP, ANG-2, VEGF) were used to make a 5-factor PFS-CBS or OS-CBS, respectively. A 2-factor CBS was generated with biomarkers common to PFS-CBS and OS-CBS. Patients were divided into groups accordingly (5-factor-CBS high: 3-5, CBS-low: 0-2; 2-factor-CBS high: 1-2, CBS-low: 0).

Results: PFS/OS with lenvatinib-plus-everolimus were significantly longer in the 5-factor CBS-high group versus the CBS-low group (P = 0.0022/P < 0.0001, respectively). In the CBS-high group, PFS/OS were significantly longer with lenvatinib-plus-everolimus versus everolimus (P < 0.001/P = 0.0079, respectively); PFS was also significantly longer with lenvatinib-plus-everolimus versus lenvatinib (P = 0.0046). The 5-factor-CBS had a predictive role in PFS and OS after multivariate analysis. Similar trends were observed with the 2-factor-CBS for PFS (i.e., lenvatinib-plus-everolimus versus everolimus).

Conclusions: The 5-factor CBS may identify patients with metastatic RCC who would benefit from lenvatinib-plus-everolimus versus everolimus; additional validation is required.

Clinical Trial Registration: The clinical trial registration number is NCT01136733.
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http://dx.doi.org/10.1038/s41416-020-01092-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7782770PMC
January 2021

NCCN Guidelines Insights: Kidney Cancer, Version 1.2021.

J Natl Compr Canc Netw 2020 09;18(9):1160-1170

National Comprehensive Cancer Network.

The NCCN Guidelines for Kidney Cancer provide multidisciplinary recommendations for diagnostic workup, staging, and treatment of patients with renal cell carcinoma (RCC). These NCCN Guidelines Insights focus on recent updates to the guidelines, including changes to certain systemic therapy recommendations for patients with relapsed or stage IV RCC. They also discuss the addition of a new section to the guidelines that identifies and describes the most common hereditary RCC syndromes and provides recommendations for genetic testing, surveillance, and/or treatment options for patients who are suspected or confirmed to have one of these syndromes.
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http://dx.doi.org/10.6004/jnccn.2020.0043DOI Listing
September 2020

The Art of Oncology: COVID-19 Era.

Oncologist 2020 11 10;25(11):997-1000g. Epub 2020 Sep 10.

Division of Hematology and Oncology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.

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http://dx.doi.org/10.1634/theoncologist.2020-0512DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7405267PMC
November 2020

Detection of renal cell carcinoma using plasma and urine cell-free DNA methylomes.

Nat Med 2020 07 22;26(7):1041-1043. Epub 2020 Jun 22.

Department of Medical Oncology, The Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.

Improving early cancer detection has the potential to substantially reduce cancer-related mortality. Cell-free methylated DNA immunoprecipitation and high-throughput sequencing (cfMeDIP-seq) is a highly sensitive assay capable of detecting early-stage tumors. We report accurate classification of patients across all stages of renal cell carcinoma (RCC) in plasma (area under the receiver operating characteristic (AUROC) curve of 0.99) and demonstrate the validity of this assay to identify patients with RCC using urine cell-free DNA (cfDNA; AUROC of 0.86).
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http://dx.doi.org/10.1038/s41591-020-0933-1DOI Listing
July 2020

Clinical and economic outcomes of treatment sequences for intermediate- to poor-risk advanced renal cell carcinoma.

Immunotherapy 2020 01 29;12(1):37-51. Epub 2020 Jan 29.

Massachusetts General Hospital Cancer Center, Boston, MA 02214, USA.

To assess the cost-effectiveness of treatment sequences for patients with intermediate- to poor-risk advanced renal cell carcinoma. A discrete event simulation model was developed to estimate patients' lifetime costs and survival. Efficacy inputs were derived from the CheckMate 214 and CheckMate 025 studies and network meta-analyses. Safety and cost data were obtained from the published literature. The estimated average quality-adjusted life-years (QALYs) gained was the highest on nivolumab + ipilimumab-initiated sequences (3.6-5.3 QALYs) versus tyrosine kinase inhibitor (TKI)-initiated sequences (2.1-3.7 QALYs). Incremental cost per QALY gained for nivolumab + ipilimumab-initiated sequences was below the willingness-to-pay threshold of $150,000 versus other sequences. Immuno-oncology combination therapy followed by TKIs is cost-effective versus TKI sequences followed by immuno-oncology or sequencing TKIs.
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http://dx.doi.org/10.2217/imt-2019-0199DOI Listing
January 2020

NCCN Guidelines Insights: Kidney Cancer, Version 2.2020.

J Natl Compr Canc Netw 2019 11;17(11):1278-1285

National Comprehensive Cancer Network.

The NCCN Guidelines for Kidney Cancer provide multidisciplinary recommendations for the clinical management of patients with clear cell and non-clear cell renal cell carcinoma, and are intended to assist with clinical decision-making. These NCCN Guidelines Insights summarize the NCCN Kidney Cancer Panel discussions for the 2020 update to the guidelines regarding initial management and first-line systemic therapy options for patients with advanced clear cell renal cell carcinoma.
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http://dx.doi.org/10.6004/jnccn.2019.0054DOI Listing
November 2019

Treatment sequences for advanced renal cell carcinoma: A health economic assessment.

PLoS One 2019 29;14(8):e0215761. Epub 2019 Aug 29.

Massachusetts General Hospital Cancer Center, Hematology/Oncology, Boston, Massachusetts, United States of America.

Objective: Advanced renal cell carcinoma (RCC) is commonly treated with vascular endothelial growth factor or mammalian target of rapamycin inhibitors. As new therapies emerge, interest grows in gaining a deeper understanding of treatment sequences. Recently, we developed a patient-level, discretely integrated condition event (DICE) simulation to estimate survival and lifetime costs for various cancer therapies, using a US payer perspective. Using this model, we explored the impact of treatments such as nivolumab and cabozantinib, and compared the clinical outcomes and cost consequences of commonly used treatment algorithms for patients with advanced RCC.

Methods: Included treatment sequences were pazopanib or sunitinib as first-line treatment, followed by nivolumab, cabozantinib, axitinib, pazopanib or everolimus. Efficacy inputs were derived from the CheckMate 025 trial and a network meta-analysis based on available literature. Safety and cost data were obtained from publicly available sources or literature.

Results: Based on our analysis, the average cost per life-year (LY) was lowest for sequences including nivolumab (sunitinib → nivolumab, $75,268/LY; pazopanib → nivolumab, $84,459/LY) versus axitinib, pazopanib, everolimus and cabozantinib as second-line treatments. Incremental costs per LY gained were $49,592, $73,927 and $30,534 for nivolumab versus axitinib, pazopanib and everolimus-containing sequences, respectively. The model suggests that nivolumab offers marginally higher life expectancy at a lower cost versus cabozantinib-including sequences.

Conclusion: Treatment sequences using nivolumab in the second-line setting are less costly compared with sequential use of targeted agents. In addition to efficacy and safety data, cost considerations may be taken into account when considering treatment algorithms for patients with advanced RCC.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0215761PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6715231PMC
March 2020

Cabozantinib Versus Sunitinib for Untreated Patients with Advanced Renal Cell Carcinoma of Intermediate or Poor Risk: Subgroup Analysis of the Alliance A031203 CABOSUN trial.

Oncologist 2019 11 9;24(11):1497-1501. Epub 2019 Aug 9.

Dana-Farber/Partners CancerCare, Boston, Massachusetts, USA.

Cabozantinib treatment prolonged progression-free survival (PFS) and improved objective response rate (ORR) compared with sunitinib in patients with advanced renal cell carcinoma (RCC) of intermediate or poor risk by International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria in the phase II CABOSUN trial (NCT01835158). In the trial, 157 patients were randomized 1:1 to receive cabozantinib or sunitinib, stratified by IMDC risk group and presence of bone metastases. Here, PFS and ORR, both determined by independent radiology committee (IRC), were analyzed by subgroups of baseline characteristics. Cabozantinib treatment was generally associated with improved PFS and ORR versus sunitinib across subgroups, including in groups defined by IMDC risk group, bone metastases, age, and tumor burden. NCT01835158.
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http://dx.doi.org/10.1634/theoncologist.2019-0316DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6853096PMC
November 2019

A Phase Ib Study of Axitinib in Combination with Crizotinib in Patients with Metastatic Renal Cell Cancer or Other Advanced Solid Tumors.

Oncologist 2019 09 6;24(9):1151-e817. Epub 2019 Jun 6.

Cleveland Clinic, Cleveland, Ohio, USA.

Lessons Learned: The combination of axitinib and crizotinib has a manageable safety and tolerability profile, consistent with the profiles of the individual agents when administered as monotherapy.The antitumor activity reported here for the combination axitinib/crizotinib does not support further study of this combination treatment in metastatic renal cell carcinoma given the current treatment landscape.

Background: Vascular endothelial growth factor (VEGF) inhibitors have been successfully used to treat metastatic renal cell carcinoma (mRCC); however, resistance eventually develops in most cases. Tyrosine protein kinase Met (MET) expression increases following VEGF inhibition, and inhibition of both has shown additive effects in controlling tumor growth and metastasis. We therefore conducted a study of axitinib plus crizotinib in advanced solid tumors and mRCC.

Methods: This phase Ib study included a dose-escalation phase (starting doses: axitinib 3 mg plus crizotinib 200 mg) to estimate maximum tolerated dose (MTD) in patients with solid tumors and a dose-expansion phase to examine preliminary efficacy in treatment-naïve patients with mRCC. Safety, pharmacokinetics, and biomarkers were also assessed.

Results: No patients in the dose-escalation phase ( = 22) experienced dose-limiting toxicity; MTD was estimated to be axitinib 5 mg plus crizotinib 250 mg. The most common grade ≥3 adverse events were hypertension (18.2%) and fatigue (9.1%). In the dose-expansion phase, overall response rate was 30% (95% confidence interval [CI], 11.9-54.3), and progression-free survival was 5.6 months (95% CI, 3.5-not reached).

Conclusion: The combination of axitinib plus crizotinib, at estimated MTD, had a manageable safety profile and showed evidence of modest antitumor activity in mRCC.
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http://dx.doi.org/10.1634/theoncologist.2018-0749DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6738313PMC
September 2019

Enhancing Antitumor Immunity with Antiangiogenic Therapy: A Clinical Model in Renal Cell Carcinoma?

Oncologist 2019 06 29;24(6):725-727. Epub 2019 Apr 29.

Department of Medicine, Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA.

Combination therapies involving antiangiogenic agents plus immune checkpoint inhibitors have recently demonstrated clinical efficacy in advanced renal cell carcinoma (RCC). This commentary summarizes the clinical advances and reviews the potential implications for RCC and other advanced solid tumors.
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http://dx.doi.org/10.1634/theoncologist.2019-0165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6656499PMC
June 2019

The future of perioperative therapy in advanced renal cell carcinoma: how can we PROSPER?

Future Oncol 2019 May 10;15(15):1683-1695. Epub 2019 Apr 10.

Department of Urology, The James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Patients with high-risk renal cell carcinoma (RCC) experience high rates of recurrence despite definitive surgical resection. Recent trials of adjuvant tyrosine kinase inhibitor therapy have provided conflicting efficacy results at the cost of significant adverse events. PD-1 blockade via monoclonal antibodies has emerged as an effective disease-modifying treatment for metastatic RCC. There is emerging data across other solid tumors of the potential efficacy of neoadjuvant PD-1 blockade, and preclinical evidence supporting a neoadjuvant over adjuvant approach. PROSPER RCC is a Phase III, randomized trial evaluating whether perioperative nivolumab increases recurrence-free survival in patients with high-risk RCC undergoing nephrectomy. The neoadjuvant component, intended to prime the immune system for enhanced efficacy, distinguishes PROSPER from other purely adjuvant studies and permits highly clinically relevant translational studies.
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http://dx.doi.org/10.2217/fon-2018-0951DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6595543PMC
May 2019

An Open Label Phase Ib Dose Escalation Study of TRC105 (Anti-Endoglin Antibody) with Axitinib in Patients with Metastatic Renal Cell Carcinoma.

Oncologist 2019 02 6;24(2):202-210. Epub 2018 Sep 6.

TRACON Pharmaceuticals, Inc., San Diego, California, USA.

Background: TRC105 is an IgG1 endoglin monoclonal antibody that potentiates VEGF inhibitors in preclinical models. We assessed safety, pharmacokinetics, and antitumor activity of TRC105 in combination with axitinib in patients with metastatic renal cell carcinoma (mRCC).

Subjects, Materials, And Methods: Heavily pretreated mRCC patients were treated with TRC105 weekly (8 mg/kg and then 10 mg/kg) in combination with axitinib (initially at 5 mg b.i.d. and then escalated per patient tolerance to a maximum of 10 mg b.i.d.) until disease progression or unacceptable toxicity using a standard 3 + 3 phase I design.

Results: Eighteen patients (median number of prior therapies = 3) were treated. TRC105 dose escalation proceeded to 10 mg/kg weekly without dose-limiting toxicity. Adverse event characteristics of each drug were not increased in frequency or severity when the two drugs were administered concurrently. TRC105 and axitinib demonstrated preliminary evidence of activity, including partial responses (PR) by RECIST in 29% of patients, and median progression-free survival (11.3 months). None of the patients with PR had PR to prior first-line treatment. Lower baseline levels of osteopontin and higher baseline levels of TGF-β receptor 3 correlated with overall response rate.

Conclusion: TRC105 at 8 and 10 mg/kg weekly was well tolerated in combination with axitinib, with encouraging evidence of activity in patients with mRCC. A multicenter, randomized phase II trial of TRC105 and axitinib has recently completed enrollment (NCT01806064).

Implications For Practice: TRC105 is a monoclonal antibody to endoglin (CD105), a receptor densely expressed on proliferating endothelial cells and also on renal cancer stem cells that is implicated as a mediator of resistance to inhibitors of the VEGF pathway. In this Phase I trial, TRC105 combined safely with axitinib at the recommended single agent doses of each drug in patients with renal cell carcinoma. The combination demonstrated durable activity in a VEGF inhibitor-refractory population and modulated several angiogenic biomarkers. A randomized Phase II trial testing TRC105 in combination with axitinib in clear cell renal cell carcinoma has completed accrual.
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http://dx.doi.org/10.1634/theoncologist.2018-0299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6369938PMC
February 2019

Application of dynamic modeling for survival estimation in advanced renal cell carcinoma.

PLoS One 2018 30;13(8):e0203406. Epub 2018 Aug 30.

Bristol-Myers Squibb, Princeton, New Jersey, United States of America.

Objective: In oncology, extrapolation of clinical outcomes beyond trial duration is traditionally achieved by parametric survival analysis using population-level outcomes. This approach may not fully capture the benefit/risk profile of immunotherapies due to their unique mechanisms of action. We evaluated an alternative approach-dynamic modeling-to predict outcomes in patients with advanced renal cell carcinoma. We compared standard parametric fitting and dynamic modeling for survival estimation of nivolumab and everolimus using data from the phase III CheckMate 025 study.

Methods: We developed two statistical approaches to predict longer-term outcomes (progression, treatment discontinuation, and survival) for nivolumab and everolimus, then compared these predictions against follow-up clinical trial data to assess their proximity to observed outcomes. For the parametric survival analyses, we selected a probability distribution based on its fit to observed population-level outcomes at 14-month minimum follow-up and used it to predict longer-term outcomes. For dynamic modeling, we used a multivariate Cox regression based on patient-level data, which included risk scores, and probability and duration of response as predictors of longer-term outcomes. Both sets of predictions were compared against trial data with 26- and 38-month minimum follow-up.

Results: Both statistical approaches led to comparable fits to observed trial data for median progression, discontinuation, and survival. However, beyond the trial duration, mean survival predictions differed substantially between methods for nivolumab (30.8 and 51.5 months), but not everolimus (27.2 and 29.8 months). Longer-term follow-up data from CheckMate 025 and phase I/II studies resembled dynamic model predictions for nivolumab.

Conclusions: Dynamic modeling can be a good alternative to parametric survival fitting for immunotherapies because it may help better capture the longer-term benefit/risk profile and support health-economic evaluations of immunotherapies.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0203406PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6117067PMC
February 2019

Radium-223 Dichloride in Combination with Vascular Endothelial Growth Factor-Targeting Therapy in Advanced Renal Cell Carcinoma with Bone Metastases.

Clin Cancer Res 2018 09 30;24(17):4081-4088. Epub 2018 May 30.

Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.

This study investigates the biologic activity of radium-223 with VEGF-targeted therapy in patients with advanced renal cell carcinoma (aRCC) and bone metastases. Fifteen treatment-naïve patients ( = 15) received pazopanib 800 mg orally once daily, and 15 previously treated patients received sorafenib 400 mg orally twice daily. Radium-223 55 kilobecquerel/kg was administered concurrently every 4 weeks for up to six infusions in both cohorts. The primary endpoint was decline in bone turnover markers (Procollagen I Intact N-Terminal, N-telopeptide, C-telopeptide, osteocalcin, and bone-specific alkaline phosphatase) compared with baseline. Secondary endpoints included safety, rate of symptomatic skeletal event (SSE) and time to first SSE, objective response rate, change in analgesic use, and quality of life. Exploratory analysis of tumor genomic alterations was performed. Of the 30 patients enrolled, 83% had IMDC intermediate- or poor-risk disease, 33% had liver metastases, and 83% had a history of SSE prior to enrollment. No dose-limiting toxicity was observed. All bone turnover markers significantly declined from baseline at week 8 and 16. Forty percent of patients experienced treatment-related grade ≥3 adverse events. Response rates were 15% and 18% per RECIST v1.1 and bone response was 50% and 30% per MD Anderson criteria, in the pazopanib and sorafenib cohort, respectively. Median SSE-free interval was 5.8 months and not reached, respectively. Analgesic use remained stable over the study time. Radium-223 combined with VEGF-targeted therapy is biologically active and safe. Randomized-controlled trials are needed to define the role of radium-223 in aRCC with skeletal metastases. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-3577DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6688176PMC
September 2018

Cabozantinib versus sunitinib as initial therapy for metastatic renal cell carcinoma of intermediate or poor risk (Alliance A031203 CABOSUN randomised trial): Progression-free survival by independent review and overall survival update.

Eur J Cancer 2018 05 20;94:115-125. Epub 2018 Mar 20.

Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Background: The randomised phase 2 CABOSUN trial comparing cabozantinib with sunitinib as initial therapy for advanced renal cell carcinoma (RCC) of intermediate or poor risk met the primary end-point of improving progression-free survival (PFS) as assessed by investigator. We report PFS by independent radiology review committee (IRC) assessment, ORR per IRC and updated overall survival (OS).

Patients And Methods: Previously untreated patients with advanced RCC of intermediate or poor risk by IMDC criteria were randomised 1:1 to cabozantinib 60 mg daily or sunitinib 50 mg daily (4 weeks on/2 weeks off). Stratification was by risk group and presence of bone metastases.

Results: A total of 157 patients were randomised 1:1 to cabozantinib (n = 79) or sunitinib (n = 78). Median PFS per IRC was 8.6 months (95% confidence interval [CI] 6.8-14.0) versus 5.3 months (95% CI 3.0-8.2) for cabozantinib versus sunitinib (hazard ratio [HR] 0.48 [95% CI 0.31-0.74]; two-sided p = 0.0008), and ORR per IRC was 20% (95% CI 12.0-30.8) versus 9% (95% CI 3.7-17.6), respectively. Subgroup analyses of PFS by stratification factors and MET tumour expression were consistent with results for the overall population. With a median follow-up of 34.5 months, median OS was 26.6 months (95% CI 14.6-not estimable) with cabozantinib and 21.2 months (95% CI 16.3-27.4) with sunitinib (HR 0.80 [95% CI 0.53-1.21]. The incidence of grade 3 or 4 adverse events was 68% for cabozantinib and 65% for sunitinib.

Conclusions: In this phase 2 trial, cabozantinib treatment significantly prolonged PFS per IRC compared with sunitinib as initial systemic therapy for advanced RCC of poor or intermediate risk.

Trial Registration Number: NCT01835158.
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http://dx.doi.org/10.1016/j.ejca.2018.02.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6057479PMC
May 2018

Durable Clinical Benefit in Metastatic Renal Cell Carcinoma Patients Who Discontinue PD-1/PD-L1 Therapy for Immune-Related Adverse Events.

Cancer Immunol Res 2018 04 1;6(4):402-408. Epub 2018 Feb 1.

Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.

The current standard of care for treatment of metastatic renal cell carcinoma (mRCC) patients is PD-1/PD-L1 inhibitors until progression or toxicity. Here, we characterize the clinical outcomes for 19 mRCC patients who experienced an initial clinical response (any degree of tumor shrinkage), but after immune-related adverse events (irAE) discontinued all systemic therapy. Clinical baseline characteristics, outcomes, and survival data were collected. The primary endpoint was time to progression from the date of treatment cessation (TTP). Most patients had clear cell histology and received anti-PD-1/PD-L1 therapy as second-line or later treatment. Median time on PD-1/PD-L1 therapy was 5.5 months (range, 0.7-46.5) and median TTP was 18.4 months (95% CI, 4.7-54.3) per Kaplan-Meier estimation. The irAEs included arthropathies, ophthalmopathies, myositis, pneumonitis, and diarrhea. We demonstrate that 68.4% of patients ( = 13) experienced durable clinical benefit off treatment (TTP of at least 6 months), with 36% ( = 7) of patients remaining off subsequent treatment for over a year after their last dose of anti-PD-1/PD-L1. Three patients with tumor growth found in a follow-up visit, underwent subsequent surgical intervention, and remain off systemic treatment. Nine patients (47.4%) have ongoing irAEs. Our results show that patients who benefitted clinically from anti-PD-1/PD-L1 therapy can experience sustained beneficial responses, not needing further therapies after the initial discontinuation of treatment due to irAEs. Investigation of biomarkers indicating sustained benefit to checkpoint blockers are needed. .
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http://dx.doi.org/10.1158/2326-6066.CIR-17-0220DOI Listing
April 2018

Long-Term Response to Sunitinib Treatment in Metastatic Renal Cell Carcinoma: A Pooled Analysis of Clinical Trials.

Clin Genitourin Cancer 2017 Jun 20. Epub 2017 Jun 20.

Gustave Roussy, Villejuif Cedex, France.

Background: We characterized clinical outcomes of patients with metastatic renal cell carcinoma (mRCC) treated with sunitinib who were long-term responders (LTRs), defined as patients having progression-free survival (PFS) > 18 months.

Patients And Methods: A retrospective analysis of data from 5714 patients with mRCC treated with sunitinib in 8 phase II/III clinical trials and the expanded access program. Duration on-study and objective response rate (ORR) were compared between LTRs and patients with PFS ≤ 18 months ("others"). PFS and overall survival (OS) were summarized using Kaplan-Meier methodology.

Results: Overall, 898 (15.7%) patients achieved a long-term response and 4816 (84.3%) patients did not achieve long-term response. The median (range) duration on-study was 28.6 (16.8-70.7) months in LTRs and 5.5 (0-68.8) months in others. ORR was 51% in LTRs versus 14% in others (P < .0001). Median PFS in LTRs was 32.11 months and median OS was not reached. LTRs had higher percentage of early tumor shrinkage ≥ 10% at the first scan (67.1% vs. 51.2%; P = .0018) and greater median maximum on-study tumor shrinkage from baseline (-56.9 vs. -27.1; P < .0001) versus others. White race, Eastern Cooperative Oncology Group performance status 0, time from diagnosis to treatment ≥ 1 year, clear cell histology, no liver metastasis, lactate dehydrogenase ≤ 1.5 upper limit of normal (ULN), corrected calcium ≤ 10 mg/dL, hemoglobin greater than the lower limit of normal, platelets less than or equal to ULN, body mass index ≥ 25 kg/m, and low neutrophil-to-lymphocyte ratio were associated with LTR.

Conclusion: A subset of patients with mRCC treated with sunitinib achieved long-term response. LTRs had improved ORR, PFS, and OS.
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http://dx.doi.org/10.1016/j.clgc.2017.06.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6736765PMC
June 2017

Kidney Cancer, Version 2.2017, NCCN Clinical Practice Guidelines in Oncology.

J Natl Compr Canc Netw 2017 06;15(6):804-834

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 guidelines are developed by a multidisciplinary panel of leading experts from NCCN Member Institutions consisting of medical oncologists, hematologists and hematologic oncologists, radiation oncologists, urologists, and pathologists. The NCCN Guidelines are in continuous evolution and are updated annually or sometimes more often, if new high-quality clinical data become available in the interim.
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http://dx.doi.org/10.6004/jnccn.2017.0100DOI Listing
June 2017

Long-term Duration of First-Line Axitinib Treatment in Advanced Renal Cell Carcinoma.

Target Oncol 2017 06;12(3):333-340

Baylor-Sammons Cancer Center, Genitourinary Oncology Program, Dallas, TX, USA.

Objective: We conducted a retrospective analysis of two clinical trials in treatment-naïve patients (n = 402) with advanced renal cell carcinoma (RCC) treated with axitinib. Our objective was to compare duration of treatment (DT) and clinical outcome in patients who achieved DT >18 months (longer DT) versus ≤18 months (shorter DT).

Patients And Methods: DT, objective response rate (ORR), tumor shrinkage, and overall survival (OS) were summarized for patients with longer and shorter DT.

Results: Overall, 152 patients (37.8%) had longer DT and 250 (62.2%) had shorter DT (median, 34.7 vs. 6.5 months, respectively). ORR in all 402 patients with advanced RCC was 43.5%. ORR was 75% for longer DT versus 24.4% for shorter DT (p < 0.0001). More patients with longer DT versus shorter DT had ≥10% tumor shrinkage at first scan (74.8% vs. 55.3%; p = 0.0001) and maximum on-study tumor shrinkage was greater in longer-DT versus shorter-DT group (-51.8% vs. -22.1%; p < 0.0001). Median OS was 32.6 months in the overall population while in the patients with longer DT the median was not reached. Treatment-related adverse events (AEs) grade ≥3 were more frequent in longer-DT versus shorter-DT and included hypertension (25.7% vs. 18.8%), diarrhea (15.1% vs. 4.4%), and weight decrease (11.2% vs. 3.2%); however, these AEs decreased over time in both groups. Eastern Cooperative Oncology Group performance status 0, favorable hematology values, no bone or liver metastases, and baseline tumor burden below the overall median were associated with longer DT.

Conclusions: Longer duration (>18 months) of axitinib treatment was associated with increased frequency of early tumor shrinkage, greater magnitude of tumor shrinkage, and a favorable OS.
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http://dx.doi.org/10.1007/s11523-017-0487-4DOI Listing
June 2017

A Phase 1/2 Trial of a Combination of Paclitaxel and Trastuzumab With Daily Irradiation or Paclitaxel Alone With Daily Irradiation After Transurethral Surgery for Noncystectomy Candidates With Muscle-Invasive Bladder Cancer (Trial NRG Oncology RTOG 0524).

Int J Radiat Oncol Biol Phys 2017 04 19;97(5):995-1001. Epub 2016 Dec 19.

Massachusetts General Hospital Cancer Center, Boston, Massachusetts.

Purpose: Bladder preservation therapy is an effective treatment for muscle-invasive urothelial carcinoma (UC). In this study we treated noncystectomy candidates with daily radiation and weekly paclitaxel for 7 weeks. Patients whose tumors showed her2/neu overexpression were additionally treated with weekly trastuzumab.

Methods And Materials: Sixty-eight evaluable patients were treated with radiation therapy and either paclitaxel + trastuzumab (group 1) or paclitaxel alone (group 2). Groups were assigned on the basis of her2/neu immunohistochemistry results. Patients received 1.8-Gy fractions to a total dose of 64.8 Gy. The primary endpoint of the study was treatment-related toxicity, and secondary endpoints included complete response (CR) rate, protocol completion rate, and survival.

Results: A total of 20 evaluable patients were treated in group 1 and 46 patients in group 2. Acute treatment-related adverse events (AEs) were observed in 7 of 20 patients in group 1 (35%) and 14 of 46 patients in group 2 (30.4%). Protocol therapy was completed by 60% (group 1) and 74% (group 2) of patients. Most incompletions were due to toxicity, and the majority of AEs were gastrointestinal, including 1 grade 5 AE (group 1). Two other deaths (both in group 2) were unrelated to protocol therapy. No unexpected cardiac, hematologic, or other toxicities were observed. The CR rate at 1 year was 72% for group 1 and 68% for group 2.

Conclusions: In patients with muscle-invasive UC who are not candidates for cystectomy, daily radiation combined with paclitaxel is an effective treatment strategy with a high completion rate and moderate toxicity. In patients with her2/neu-positive tumors, a group generally considered to have worse outcomes, the addition of trastuzumab appears to result in comparable efficacy and toxicity. Further biomarker-driven trials should be undertaken in advancing treatment of this challenging disease.
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http://dx.doi.org/10.1016/j.ijrobp.2016.12.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5536836PMC
April 2017

The prospective impact of food pricing on improving dietary consumption: A systematic review and meta-analysis.

PLoS One 2017 1;12(3):e0172277. Epub 2017 Mar 1.

Friedman School of Nutrition Science & Policy, Tufts University, Boston, MA, United States of America.

Background: While food pricing is a promising strategy to improve diet, the prospective impact of food pricing on diet has not been systematically quantified.

Objective: To quantify the prospective effect of changes in food prices on dietary consumption.

Design: We systematically searched online databases for interventional or prospective observational studies of price change and diet; we also searched for studies evaluating adiposity as a secondary outcome. Studies were excluded if price data were collected before 1990. Data were extracted independently and in duplicate. Findings were pooled using DerSimonian-Laird's random effects model. Pre-specified sources of heterogeneity were analyzed using meta-regression; and potential for publication bias, by funnel plots, Begg's and Egger's tests.

Results: From 3,163 identified abstracts, 23 interventional studies and 7 prospective cohorts with 37 intervention arms met inclusion criteria. In pooled analyses, a 10% decrease in price (i.e., subsidy) increased consumption of healthful foods by 12% (95%CI = 10-15%; N = 22 studies/intervention arms) whereas a 10% increase price (i.e. tax) decreased consumption of unhealthful foods by 6% (95%CI = 4-8%; N = 15). By food group, subsidies increased intake of fruits and vegetables by 14% (95%CI = 11-17%; N = 9); and other healthful foods, by 16% (95%CI = 10-23%; N = 10); without significant effects on more healthful beverages (-3%; 95%CI = -16-11%; N = 3). Each 10% price increase reduced sugar-sweetened beverage intake by 7% (95%CI = 3-10%; N = 5); fast foods, by 3% (95%CI = 1-5%; N = 3); and other unhealthful foods, by 9% (95%CI = 6-12%; N = 3). Changes in price of fruits and vegetables reduced body mass index (-0.04 kg/m2 per 10% price decrease, 95%CI = -0.08-0 kg/m2; N = 4); price changes for sugar-sweetened beverages or fast foods did not significantly alter body mass index, based on 4 studies. Meta-regression identified direction of price change (tax vs. subsidy), number of intervention components, intervention duration, and study quality score as significant sources of heterogeneity (P-heterogeneity<0.05 each). Evidence for publication bias was not observed.

Conclusions: These prospective results, largely from interventional studies, support efficacy of subsidies to increase consumption of healthful foods; and taxation to reduce intake of unhealthful beverages and foods. Use of subsidies and combined multicomponent interventions appear most effective.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0172277PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5332034PMC
August 2017

Cabozantinib Versus Sunitinib As Initial Targeted Therapy for Patients With Metastatic Renal Cell Carcinoma of Poor or Intermediate Risk: The Alliance A031203 CABOSUN Trial.

J Clin Oncol 2017 02 14;35(6):591-597. Epub 2016 Nov 14.

Toni K. Choueiri and Meghara K. Walsh, Dana-Farber Cancer Institute; M. Dror Michaelson, Massachusetts General Hospital Cancer Center, Boston, MA; Susan Halabi and Ben L. Sanford, Alliance Statistics and Data Center and Duke University; Daniel J. George, Duke Cancer Institute, Duke University Medical Center, Durham, NC; Olwen Hahn, Alliance Protocol Operations Office, Chicago, IL; Darren R. Feldman and Michael J. Morris, Memorial Sloan Kettering Cancer Center, New York, NY; Thomas Olencki, Ohio State University Medical Center, Columbus, OH; Joel Picus, Siteman Cancer Center, Washington University School of Medicine, St Louis, MO; Eric J. Small, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA; and Shaker Dakhil, University of Kansas Wichita, Wichita, KS.

Purpose Cabozantinib is an oral potent inhibitor of vascular endothelial growth factor receptor 2, MET, and AXL and is a standard second-line therapy for metastatic renal cell carcinoma (mRCC). This randomized phase II multicenter trial evaluated cabozantinib compared with sunitinib as first-line therapy in patients with mRCC. Patients and Methods Eligible patients had untreated clear cell mRCC and Eastern Cooperative Oncology Group performance status of 0 to 2 and were intermediate or poor risk per International Metastatic Renal Cell Carcinoma Database Consortium criteria. Patients were randomly assigned at a one-to-one ratio to cabozantinib (60 mg once per day) or sunitinib (50 mg once per day; 4 weeks on, 2 weeks off). Progression-free survival (PFS) was the primary end point. Objective response rate (ORR), overall survival, and safety were secondary end points. Results From July 2013 to April 2015, 157 patients were randomly assigned (cabozantinib, n = 79; sunitinib, n = 78). Compared with sunitinib, cabozantinib treatment significantly increased median PFS (8.2 v 5.6 months) and was associated with a 34% reduction in rate of progression or death (adjusted hazard ratio, 0.66; 95% CI, 0.46 to 0.95; one-sided P = .012). ORR was 33% (95% CI, 23 to 44) for cabozantinib versus 12% (95% CI, 5.4 to 21) for sunitinib. All-causality grade 3 or 4 adverse events were 67% for cabozantinib and 68% for sunitinib and included diarrhea (cabozantinib, 10% v sunitinib, 11%), fatigue (6% v 15%), hypertension (28% v 22%), palmar-plantar erythrodysesthesia (8% v 4%), and hematologic adverse events (3% v 22%). Conclusion Cabozantinib demonstrated a significant clinical benefit in PFS and ORR over standard-of-care sunitinib as first-line therapy in patients with intermediate- or poor-risk mRCC.
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http://dx.doi.org/10.1200/JCO.2016.70.7398DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5455807PMC
February 2017

Prescribing error at hospital discharge: a retrospective review of medication information in an Irish hospital.

Ir J Med Sci 2017 Aug 30;186(3):795-800. Epub 2017 Jan 30.

School of Pharmacy, University College Cork, Cork, Ireland.

Background: Prescribing error may result in adverse clinical outcomes leading to increased patient morbidity, mortality and increased economic burden. Many errors occur during transitional care as patients move between different stages and settings of care.

Aim: To conduct a review of medication information and identify prescribing error among an adult population in an urban hospital.

Methods: Retrospective review of medication information was conducted. Part 1: an audit of discharge prescriptions which assessed: legibility, compliance with legal requirements, therapeutic errors (strength, dose and frequency) and drug interactions. Part 2: A review of all sources of medication information (namely pre-admission medication list, drug Kardex, discharge prescription, discharge letter) for 15 inpatients to identify unintentional prescription discrepancies, defined as: "undocumented and/or unjustified medication alteration" throughout the hospital stay.

Results: Part 1: of the 5910 prescribed items; 53 (0.9%) were deemed illegible. Of the controlled drug prescriptions 11.1% (n = 167) met all the legal requirements. Therapeutic errors occurred in 41% of prescriptions (n = 479) More than 1 in 5 patients (21.9%) received a prescription containing a drug interaction. Part 2: 175 discrepancies were identified across all sources of medication information; of which 78 were deemed unintentional. Of these: 10.2% (n = 8) occurred at the point of admission, whereby 76.9% (n = 60) occurred at the point of discharge.

Conclusions: The study identified the time of discharge as a point at which prescribing errors are likely to occur. This has implications for patient safety and provider work load in both primary and secondary care.
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http://dx.doi.org/10.1007/s11845-017-1556-5DOI Listing
August 2017

Long-term Outcomes After Bladder-preserving Tri-modality Therapy for Patients with Muscle-invasive Bladder Cancer: An Updated Analysis of the Massachusetts General Hospital Experience.

Eur Urol 2017 06 9;71(6):952-960. Epub 2017 Jan 9.

Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA, USA. Electronic address:

Background: Tri-modality therapy (TMT) is a recognized treatment strategy for selected patients with muscle-invasive bladder cancer (MIBC).

Objective: Report long-term outcomes of patients with MIBC treated by TMT.

Design, Setting, And Participants: Four hundred and seventy-five patients with cT2-T4a MIBC were enrolled on protocols or treated as per protocol at the Massachusetts General Hospital between 1986 and 2013.

Intervention: Patients underwent transurethral resection of bladder tumor followed by concurrent radiation and chemotherapy. Patients with less than a complete response (CR) to chemoradiation or with an invasive recurrence were recommended to undergo salvage radical cystectomy.

Outcome Measurements And Statistical Analysis: Disease-specific survival (DSS) and overall survival (OS) were calculated using the Kaplan-Meier method.

Results And Limitations: Median follow-up for surviving patients was 7.21 yr. Five- and 10-yr DSS rates were 66% and 59%, respectively. Five- and 10-yr OS rates were 57% and 39%, respectively. The risk of salvage cystectomy at 5 yr was 29%. In multivariate analyses, T2 disease (OS hazard ratio [HR]: 0.57, 95% confidence interval [CI]: 0.44-0.75, DSS HR: 0.51, 95% CI: 0.36-0.73), CR to chemoradiation (OS HR: 0.61, 95% CI: 0.46-0.81, DSS HR: 0.49, 95% CI: 0.34-0.71), and presence of tumor-associated carcinoma in situ (OS HR: 1.56, 95% CI: 1.17-2.08, DSS HR: 1.50, 95% CI: 1.03-2.17) were significant predictors for OS and DSS. When evaluating our cohort over treatment eras, rates of CR improved from 66% to 88% and 5-yr DSS improved from 60% to 84% during the eras of 1986-1995 to 2005-2013, while the 5-yr risk of salvage radical cystectomy rate decreased from 42% to 16%.

Conclusions: These data demonstrate high rates of CR and bladder preservation in patients receiving TMT, and confirm DSS rates similar to modern cystectomy series. Contemporary results are particularly encouraging, and therefore TMT should be discussed and offered as a treatment option for selected patients.

Patient Summary: Tri-modality therapy is an alternative to radical cystectomy for patients with muscle-invasive bladder cancer, and is associated with comparable long-term survival and high rates of bladder preservation.
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http://dx.doi.org/10.1016/j.eururo.2016.12.020DOI Listing
June 2017

Heterogeneity of Patients With Intermediate-Prognosis Metastatic Renal Cell Carcinoma Treated With Sunitinib.

Clin Genitourin Cancer 2017 04 18;15(2):291-299.e1. Epub 2016 Aug 18.

Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA.

Background: The Memorial Sloan Kettering Cancer Center (MSKCC) and International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) models categorize patients with 1 or 2 risk factors as intermediate prognosis (INTMP). This category encompasses 15 and 19 permutations of the MSKCC and IMDC risk factors, respectively. The purpose of the present retrospective analysis of data from INTMP patients in 6 clinical trials was to determine whether this heterogeneity influences the response to sunitinib.

Patients And Methods: Patients with INTMP metastatic renal cell carcinoma (mRCC) were identified using the MSKCC and IMDC classifications. The statistical data were analyzed using Cox regression analysis, Kaplan-Meier methods, and Pearson χ tests.

Results: The patient characteristics and risk factors were similar in the MSKCC (n = 548) and IMDC (n = 517) groups. Overall, 59% had 1 risk factor and 41% had 2 risk factors. The most common was low hemoglobin alone or with an interval of < 1 year since diagnosis. In both groups, patients with 1 risk factor had longer overall survival (OS) and progression-free survival (PFS) than did those with 2 risk factors (P < .001 for both outcomes). Patients in the IMDC group with 1 risk factor had a greater objective response rate (ORR; P = .023). In both groups, OS was longer for patients with Eastern Cooperative Oncology Group performance status (ECOG PS) 0 than for those with ECOG PS 1 or 2 (P < .001). An ECOG PS of 0 was also associated with superior PFS and ORR in the MSKCC group (P < .05).

Conclusion: INTMP comprises a heterogeneous group of mRCC patients in whom the number of risk factors and ECOG PS might predict the outcome with sunitinib.
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http://dx.doi.org/10.1016/j.clgc.2016.08.013DOI Listing
April 2017

Phase 2 Study of Bevacizumab and Temsirolimus After VEGFR TKI in Metastatic Renal Cell Carcinoma.

Clin Genitourin Cancer 2016 08 23;14(4):304-313.e6. Epub 2016 Feb 23.

Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA. Electronic address:

Background: Inhibiting VEGF and mammalian target of rapamycin (mTOR) pathways are standard treatment approaches for patients with metastatic renal cell carcinoma (mRCC). Here we report the activity and safety of the VEGF ligand inhibitor bevacizumab and the mTOR inhibitor temsirolimus combination in patients with clear cell (CC) and non-clear cell (NCC) mRCC whose disease had failed to respond to prior VEGF blockade.

Patients And Methods: In this phase 2 investigator-initiated multicenter study, patients received bevacizumab and temsirolimus. The primary end point was 4-month progression-free survival (PFS) rate. Secondary end points included overall response rate, median overall survival (OS), toxicity, and correlative studies of biomarkers downstream of mTOR.

Results: Forty patients received at least 1 dose of therapy. Thirty-three (82.5%) had favorable/intermediate risk disease according to International Metastatic Renal Cell Carcinoma Database Consortium criteria, 13 (32.5%) with nccRCC histology. Nineteen (48.7%) had primary vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI)-refractory disease. The 4-month PFS rate was 65%. Overall median PFS and OS were 5.6 and 12.2 months. Median PFS and OS were 6.5 and 9.6 months in patients with primary VEGFR TKI-refractory disease, and 5.6 months and 13.1 months in patients with nccRCC. Dose reductions were needed in 80% of patients. Most frequent toxicities included fatigue, hypertension, dyslipidemia, and proteinuria. Dose discontinuation due to adverse events occurred in 27.5% of patients. Baseline tumor immunohistochemistry for phospho-S6 protein was not associated with clinical benefit.

Conclusion: Combining bevacizumab and temsirolimus in patients previously treated with VEGFR TKI was possible but with dose reductions and treatment discontinuations. This combination resulted in modest activity, including in patients with primary VEGF-refractory disease and NCC histology.
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http://dx.doi.org/10.1016/j.clgc.2016.02.007DOI Listing
August 2016

Three Synchronous Atypical Metastases of Clear Cell Renal Carcinoma to the Maxillary Gingiva, Scalp and the Distal Phalanx of the Fifth Digit: A Case Report.

J Oral Maxillofac Surg 2016 Jun 13;74(6):1286.e1-9. Epub 2016 Feb 13.

Associate Professor, Department of Oral and Maxillofacial Surgery, Massachusetts General Hospital and Harvard School of Dental Medicine, Boston, MA.

Oral cavity metastasis of malignant tumors is extremely rare and accounts for only 1% of all malignant oral tumors. Renal cell carcinoma (RCC) can metastasize to any part of the body, with a 15% risk of metastasis to the head and neck region when the disease is disseminated and a 1% risk when it is not. RCC also is the third most common infraclavicular neoplasm that metastasizes to the oral cavity, after lung carcinoma in men and breast carcinoma in women. In the maxillofacial region, the nasal cavity and paranasal sinuses are the most commonly affected sites, followed by the oral cavity. This report describes the case of a 51-year-old man with a history of clear RCC presenting with 3 synchronous atypical metastases of this tumor to the maxillary gingiva, scalp, and distal phalanx of the fifth digit. Clinical findings, diagnosis, pathology, and treatment of these lesions are discussed. Metastasis of RCC should always be included in the differential diagnosis when a new oral and maxillofacial lesion appears in a patient with a history of RCC because the metastatic lesions can often present in a broad spectrum of forms. The rapid growth of these lesions should alert clinicians to avoid any delays in biopsy examination and subsequent treatment, which is usually palliative, because prognosis is usually poor.
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http://dx.doi.org/10.1016/j.joms.2016.01.054DOI Listing
June 2016