Zhimei Liu

Burden of disease and unmet needs in tuberous sclerosis complex with neurological manifestations: systematic review

Abstract Objectives: Tuberous sclerosis complex (TSC) is a progressive genetic disorder characterized by pervasive benign tumor growth. We sought to assess the current understanding of burden of TSC-related neurological manifestations. Methods: We systematically searched MEDLINE- and EMBASE-indexed, English-language literature (5/2000−5/2010) and non-indexed materials. Results: In total, 119 articles were included, 115 on epidemiology and treatment. Recent prevalence estimates from Ireland and Taiwan report TSC in 1:14,000−25,000 individuals, below older estimates of 1:10,000. While neurological manifestations are common, treatment is largely unaddressed by guidelines and focuses on symptoms, with resection standard for subependymal giant cell astrocytomas (SEGAs) and common practice for refractory epilepsy. Antiepileptic drugs and mammalian target of rapamycin inhibitors safely, effectively minimize the need for surgery for severe epilepsy and SEGAs. Conclusion: Morbidity and treatment burden of prevalent neurological manifestations is significant, suggesting substantial economic and humanistic burden; however, these areas are poorly studied, indicating total disease burden is unknown. Future research should assess quality of life, caregiver burden, and costs.

Comparative outcomes of everolimus, temsirolimus and sorafenib as second targeted therapies for metastatic renal cell carcinoma: a US medical record review

Abstract Objective: To compare outcomes of metastatic renal cell carcinoma (mRCC) patients treated with everolimus, temsirolimus, and sorafenib following initial treatment with a tyrosine kinase inhibitor (TKI) in community and academic practices throughout the US. Research design and methods: Medical records of mRCC patients who received everolimus, temsirolimus or sorafenib as their second therapy following a TKI were retrospectively reviewed from a nationally representative panel of oncologists. Overall survival (OS) and progression-free survival (PFS) of second targeted therapies were compared using multivariable Cox proportional hazard models, with adjustment for demographics, disease severity and prior treatments. Results: A total of 233, 178, and 123 mRCC patients receiving everolimus, temsirolimus, and sorafenib, respectively, as second targeted therapies were included. Eighty-six percent used sunitinib and the remainder used sorafenib or pazopanib as their initial TKI. After adjusting for baseline characteristics, everolimus was associated with significantly prolonged OS (hazard ratio [HR] 0.60; CI 0.42–0.85; p = 0.004) and PFS (HR 0.73; CI 0.54–0.97; p = 0.032) compared to temsirolimus. Everolimus was associated with significantly longer OS (HR 0.66; CI 0.44–0.99; p = 0.045) and numerically longer PFS compared to sorafenib. No significant differences were observed between temsirolimus and sorafenib. Limitations: Despite adjustment for multiple patient characteristics, comparisons between treatment groups may be confounded by unobserved factors in this retrospective observational study. Tolerability outcomes were not collected. Conclusions: In this retrospective, non-randomized study of mRCC patients with prior TKI treatment, everolimus was associated with significantly prolonged OS and PFS compared to temsirolimus and significantly prolonged OS compared to sorafenib.

Patients rank toxicity against progression free survival in second-line treatment of advanced renal cell carcinoma

Abstract Background: The aims of this study were to quantify and contrast patient preferences between second-line advanced renal cell carcinoma (RCC) medication profiles and their associated benefits and toxicities, and to help frame the doctor–patient discussion about selecting appropriate RCC therapies. Research design and methods: Adult residents of the US with a diagnosis of RCC completed a Web-enabled choice-format conjoint survey consisting of a series of 10 treatment-choice questions, each of which included a pair of hypothetical RCC medication profiles. Each profile was described by various medication attributes (features or outcomes) with varying levels. The attributes included efficacy (progression-free survival [PFS]), tolerability (fatigue, stomach problems, mucositis or stomatitis, hand–foot syndrome [HFS]), serious but rare adverse events (pneumonitis, hepatic impairment), and mode of administration. Treatment-choice questions were based on an experimental design with known statistical properties. Random-parameters logit regression was used to estimate relative preference weights for each attribute level. Benefit equivalent measures (additional months of PFS in exchange for toxicities) were also calculated. Results: Of the 272 patients who completed the survey, the majority were female (53%), white (92%), and had at least a college degree (66%). The mean age was 57 years (standard deviation: 10 years). Over the range of attributes and attribute levels included in the survey, PFS was the most important attribute, followed by fatigue, stomach problems, hepatic impairment, mucositis or stomatitis, HFS, pneumonitis, and mode of administration. To reduce severe fatigue to mild-to-moderate fatigue, patients on average would be willing to forego 4.4 months of PFS. To reduce hepatic impairment risk from 0.5% to 0.0%, patients on average would be willing to forego 1.0 month of PFS. The main study limitation was that patients answered hypothetical treatment-choice questions. Conclusions: This study provides information to physicians about patient priorities when reviewing and selecting RCC therapies with patients.

Treatment patterns in metastatic renal cell carcinoma: a retrospective review of medical records from US community oncology practices

Abstract Background: Vascular endothelial growth factor (VEGF) inhibitors, including targeted therapy with tyrosine kinase inhibitors (TKIs) and the angiogenesis inhibitor bevacizumab, and mammalian target of rapamycin (mTOR) inhibitors are now the standard of care for metastatic renal cell carcinoma (mRCC). However, real-world treatment patterns are not well characterized. Objective: To describe treatment patterns during the first, second, and third lines of targeted therapies for mRCC among community oncologists in the US. Methods: Participating physicians recruited from a nationwide panel each identified up to 15 adult mRCC patients who initiated a second therapy after January 2010. Information extracted from medical records included types of targeted therapies, reasons for treatment choices, patterns of treatment discontinuation, and dose adjustments. Results: Thirty-six physicians contributed charts from 433 mRCC patients. Seventy-seven percent of patients received a VEGF inhibitor as first targeted therapy; 23% received an mTOR inhibitor. Among first-line VEGF users, second-line treatments were 66% mTOR and 34% VEGF inhibitors. Among first-line mTOR users, second-line treatments were 94% VEGF and 6% mTOR inhibitors. Sunitinib followed by everolimus was the most commonly used treatment sequence. Estimated median duration for second targeted therapy was 8.6 months, and median overall survival (OS) and progression-free survival (PFS) were 27.4 and 10.8 months, respectively. Efficacy, treatment guidelines and mechanism of action were the most important considerations for treatment choice. Limitations: Limitations include no adjustment for baseline characteristics, possible difference between physician-defined progression and central review in the clinical trial setting, and limited data availability for axitinib during the study period. Conclusion: In this large retrospective chart review among community oncologists, VEGF–mTOR–VEGF was the most common treatment sequence for mRCC. The most common drugs were sunitinib in the first line and everolimus in the second line.

An adjusted indirect comparison of everolimus and sorafenib therapy in sunitinib-refractory metastatic renal cell carcinoma patients using repeated matched samples

Objective: To date, no trial data exist comparing treatment outcomes for everolimus versus sorafenib. The current analysis indirectly compares the overall survival (OS) benefit of everolimus and sorafenib as second-line treatment options. Research design and methods: A single-arm sorafenib study is selected as a basis to match an everolimus sunitinib-refractory subpopulation of the RECORD-1 trial. Only patients with clear cell histology are included. An adjusted matching approach is taken where 1000 repeated random samples matched to the sorafenib population on risk score distribution are produced, and a 95% CI around the mean of all sampled median OS is generated. Main outcome measures: The main outcome measures include adjusted median OS and progression-free survival. Results: In all, 45 clear cell histology sorafenib patients and 1000 samples of N = 41 sunitinib-refractory everolimus patients are considered for analysis. After adjusted matching, the estimated median OS benefit is 32.7 weeks (95% CI: 22, 64) and 81.5 weeks (95% CI: 78, 86) for sorafenib and everolimus patients, respectively. Conclusion: Results suggest that sunitinib-refractory metastatic renal cell carcinoma patients treated with everolimus may experience significantly improved OS outcomes compared to those treated with sorafenib. However, because this is not a randomized controlled trial, the results should be interpreted as those from an observational study.

Economic evaluation of everolimus versus sorafenib for the treatment of metastatic renal cell carcinoma after failure of first-line sunitinib.

BACKGROUND A recent indirect comparison study showed that sunitinib-refractory metastatic renal cell carcinoma (mRCC) patients treated with everolimus are expected to have improved overall survival outcomes compared to patients treated with sorafenib. This analysis examines the likely cost-effectiveness of everolimus versus sorafenib in this setting from a US payer perspective. METHODS A Markov model was developed to simulate a cohort of sunitinib-refractory mRCC patients and to estimate the cost per incremental life-years gained (LYG) and quality-adjusted life-years (QALYs) gained. Markov states included are stable disease without adverse events, stable disease with adverse events, disease progression, and death. Transition probabilities were estimated using a subset of the RECORD-1 patient population receiving everolimus after sunitinib, and a comparable population receiving sorafenib in a single-arm phase II study. Costs of antitumor therapies were based on wholesale acquisition cost. Health state costs accounted for physician visits, tests, adverse events, postprogression therapy, and end-of-life care. The model extrapolated beyond the trial time horizon for up to 6 years based on published trial data. Deterministic and probabilistic sensitivity analyses were conducted. RESULTS The estimated gain over sorafenib treatment was 1.273 LYs (0.916 QALYs) at an incremental cost of

Cost-effectiveness of everolimus vs sunitinib in treating patients with advanced, progressive pancreatic neuroendocrine tumors in the United States

81,643. The deterministic analysis resulted in an incremental cost-effectiveness ratio (ICER) of

Comparative effectiveness of second-line targeted therapies for metastatic renal cell carcinoma: synthesis of findings from two multi-practice chart reviews in the United States

64,155/LYG (

Everolimus vs. Temsirolimus for Advanced Renal Cell Carcinoma: Use and Use of Resources in the US Oncology Network

89,160/QALY). The probabilistic sensitivity analysis demonstrated that results were highly consistent across simulations. CONCLUSIONS As the ICER fell within the cost per QALY range for many other widely used oncology medicines, everolimus is projected to be a cost-effective treatment relative to sorafenib for sunitinib-refractory mRCC.

Long-term Clinical Morbidity in Patients With Renal Angiomyolipoma Associated With Tuberous Sclerosis Complex

Abstract Background: Everolimus (Afinitor) and sunitinib (Sutent) were recently approved to treat patients with advanced, progressive pancreatic neuroendocrine tumors (pNETs). (Afinitor is a registered trademark of Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA; Sutent is a registered trademark of Pfizer Inc., New York, NY, USA.) This analysis examined the projected cost-effectiveness of everolimus vs sunitinib in this setting from a US payer perspective. Methods: A semi-Markov model was developed to simulate a cohort of patients with advanced, progressive pNET and to estimate the cost per life-year gained (LYG) and per quality-adjusted life-year (QALY) gained when treating with everolimus vs sunitinib. Efficacy data were based on a weight-adjusted indirect comparison of the agents using phase 3 trial data. Model health states included: stable disease with no adverse events, stable disease with adverse events, disease progression, and death. Therapy costs were based on wholesale acquisition cost. Other costs such as physician visits, tests, hospitalizations, and adverse event costs were obtained from literature and/or primary research. Utility inputs were based on primary research. Sensitivity analyses were conducted to test the model’s robustness. Results: In the base-case analysis, everolimus was associated with an incremental 0.448 LYG (0.304 QALYs) at an incremental cost of