Claudie Charbonneau

Epidemiologic and socioeconomic burden of metastatic renal cell carcinoma (mRCC): A literature review

Renal cell carcinoma (RCC), the most common form of kidney cancer, initially has an asymptomatic clinical course; 25-30% of patients present with metastatic disease at time of diagnosis. Worldwide incidence and mortality rates are rising at a rate of approximately 2-3% per decade. Metastatic RCC (mRCC) is one of the most treatment-resistant malignancies; outcomes are generally poor and median survival after diagnosis is less than one year. Surgery and chemotherapy have limited or no effect, leaving mRCC patients underserved in the realm of cancer treatment. As the worlds population ages and the prevalence of risk factors (obesity, hypertension) increases, the burden of mRCC is predicted to increase significantly. With a shift in treatment of mRCC to novel therapies, such as molecularly targeted therapies (MTTs) (e.g., sorafenib and sunitinib), clinicians, payers, and other healthcare decision-makers must re-evaluate the optimal role for new treatments. Timely understanding of the burden of mRCC on individuals and society clearly is needed at this juncture. Using a comprehensive literature review, we assessed the epidemiologic, economic, and health-related quality of life (HRQOL) burdens of mRCC. The annual incidence of mRCC in major European countries, the US, and Japan ranges from 1500 to 8600 cases. However, prevalence data were lacking. The estimated economic burden of mRCC is large;

Quality of life in patients with metastatic renal cell carcinoma treated with sunitinib or interferon alfa: Results from a phase III randomized trial

107-

Multicenter, Randomized Phase II Trial of Oral CI-1033 for Previously Treated Advanced Ovarian Cancer

556 million (2006 USD) in the US and

Health-related quality of life in patients with metastatic renal cell carcinoma treated with sunitinib vs interferon- α in a phase III trial: final results and geographical analysis

446 million-

Clinical and economic burden of invasive fungal diseases in Europe: focus on pre-emptive and empirical treatment of Aspergillus and Candida species.

1.6 billion (2006 USD) collectively in select countries worldwide. MTTs have potential to reduce the burden of mRCC and provide substantial value beyond their clinical effectiveness.

Analyzing Overall Survival in Randomized Controlled Trials with Crossover and Implications for Economic Evaluation

PURPOSE In an international, randomized phase III trial, sunitinib demonstrated statistically significant efficacy over interferon alfa (IFN-alpha) as first-line therapy in patients with metastatic renal cell carcinoma (mRCC) (progression-free survival time, 11 v 5 months, respectively; P < .001; objective response rate, 31% v 6%, respectively; P < .001). We report health-related quality-of-life (QOL) results from this trial. PATIENTS AND METHODS Seven hundred fifty mRCC patients were randomly assigned to sunitinib (6-week cycles: 50 mg orally once daily for 4 weeks, followed by 2 weeks off) or IFN-alpha (9 million units subcutaneous injections, three times weekly). QOL measures included the Functional Assessment of Cancer Therapy-General (FACT-G), the FACT-Kidney Symptom Index-15 item (FKSI-15), and the EuroQoL-5Ds utility score (EQ-5D Index) and its visual analog scale (EQ-VAS). The primary QOL end point was the FKSI Disease-Related Symptoms (FKSI-DRS) subscale. Higher scores indicated better outcomes (better QOL or fewer symptoms). Data were analyzed for the intent-to-treat population using mixed-effects models, supplemented with pattern-mixture models. RESULTS Patients receiving sunitinib reported higher FKSI-15 and FKSI-DRS scores at each cycle than those receiving IFN-alpha, with a significant difference in the overall least squares means (3.27 and 1.98, respectively; P < .0001). Similarly, differences in least squares means for FACT-G (and all subscales), EQ-5D Index, and EQ-VAS were all significantly favorable for sunitinib (P < .01). Per pre-established thresholds, between-treatment differences in the mean scores were clinically meaningful after cycle 4 for FKSI-DRS and at all assessments for FKSI-15, FACT-G, and the FACT-G functional well-being subscale. CONCLUSION Sunitinib provides superior QOL compared with IFN-alpha in mRCC patients.

Antibiotic treatment patterns across Europe in patients with complicated skin and soft-tissue infections due to meticillin-resistant Staphylococcus aureus: a plea for implementation of early switch and early discharge criteria.

PURPOSE To evaluate the antitumor activity and toxicity of two doses of CI-1033 in patients with platinum-refractory or recurrent ovarian cancer, and to determine baseline expression of epidermal growth factor receptor in tumor cells. PATIENTS AND METHODS This phase II, open-label clinical trial evaluated CI-1033 in patients with ovarian cancer who failed prior platinum-based therapy. Two oral doses of CI-1033 were evaluated--a 50-mg and a 200--mg oral dose administered daily for 21 days in a 28-day cycle. Patients were evaluated for tumor response and toxicity; in addition, archival baseline tumor samples were analyzed by immunohistochemistry for erbB1 to erbB4 status. RESULTS One hundred five eligible patients were treated. Baseline demographic characteristics were balanced in this heavily pretreated patient population. The median number of prior chemotherapy regimens received was four. The most commonly encountered drug-related adverse events for both dose arms were gastrointestinal (diarrhea, nausea, stomatitis) toxicity, asthenia, and rash. No responses were observed. Stable disease was confirmed in 34% and 26% of patients in the 200-mg and 50-mg arms, respectively, and 1-year survival rates were 38.5% and 37.7%, respectively. Baseline erbB3 and erbB4 revealed the highest frequencies of expression, while erbB2 was the lowest. CONCLUSION CI-1033 did not show activity in unscreened patients with advanced ovarian cancer. At 50 mg/d, CI-1033 had a more favorable adverse events profile than at 200 mg/d. erbB3 and erbB4 receptors showed the highest expression in tumor samples while erbB2 revealed the least. There appears to be no association between baseline erbB expression and disease stability.

Economic evaluation of new targeted therapies for the first-line treatment of patients with metastatic renal cell carcinoma.

Background:In a randomised phase III trial, sunitinib significantly improved efficacy over interferon-α (IFN-α) as first-line therapy for metastatic renal cell carcinoma (mRCC). We report the final health-related quality of life (HRQoL) results.Methods:Patients (n=750) received oral sunitinib 50 mg per day in 6-week cycles (4 weeks on, 2 weeks off treatment) or subcutaneous IFN-α 9 million units three times weekly. Health-related quality of life was assessed with nine end points: the Functional Assessment of Cancer Therapy–General and its four subscales, FACT–Kidney Symptom Index (FKSI-15) and its Disease-Related Symptoms subscale (FKSI-DRS), and EQ-5D questionnaires EQ-5D Index and visual analogue scale. Data were analysed using mixed-effects model (MM), supplemented with pattern-mixture models (PMM), for the total sample and the US and European Union (EU) subgroups.Results:Patients receiving sunitinib reported better scores in the primary end point, FKSI-DRS, across all patient populations (P<0.05), and in nine, five, and six end points in the total sample, in the US and EU groups respectively (P<0.05). There were no significant differences between the US and EU groups for all end points with the exception of the FKSI item ‘I am bothered by side effects of treatment’ (P=0.02). In general, MM and PMM results were similar.Conclusion:Patients treated with sunitinib in this study had improved HRQoL, compared with patients treated with IFN-α. Treatment differences within the US cohort did not differ from those within the EU cohort.

Quality of Life Predicts Progression-Free Survival in Patients With Metastatic Renal Cell Carcinoma Treated With Sunitinib Versus Interferon Alfa

Invasive fungal diseases (IFDs) have been widely studied in recent years, largely because of the increasing population at risk. Aspergillus and Candida species remain the most common causes of IFDs, but other fungi are emerging. The early and accurate diagnosis of IFD is critical to outcome and the optimisation of treatment. Rapid diagnostic methods and new antifungal therapies have advanced disease management in recent years. Strategies for the prevention and treatment of IFDs include prophylaxis, and empirical and pre-emptive therapy. Here, we review the available primary literature on the clinical and economic burden of IFDs in Europe from 2000 to early 2011, with a focus on the value and outcomes of different approaches.

Pathophysiology and burden of infection in patients with diabetes mellitus and peripheral vascular disease: focus on skin and soft-tissue infections

BACKGROUND Offering patients in oncology trials the opportunity to cross over to active treatment at disease progression is a common strategy to address ethical issues associated with placebo controls but may lead to statistical challenges in the analysis of overall survival and cost-effectiveness because crossover leads to information loss and dilution of comparative clinical efficacy. OBJECTIVES We provide an overview of how to address crossover, implications for risk-effect estimates of survival (hazard ratios) and cost-effectiveness, and how this influences decisions of reimbursement agencies. Two case studies using data from two phase III sunitinib oncology trials are used as illustration. METHODS We reviewed the literature on statistical methods for adjusting for crossover and recent health technology assessment decisions in oncology. RESULTS We show that for a trial with a high proportion of crossover from the control arm to the investigational arm, the choice of the statistical method greatly affects treatment-effect estimates and cost-effectiveness because the range of relative mortality risk for active treatment versus control is broad. With relatively frequent crossover, one should consider either the inverse probability of censoring weighting or the rank-preserving structural failure time model to minimize potential bias, with choice dependent on crossover characteristics, trial size, and available data. A large proportion of crossover favors the rank-preserving structural failure time model, while large sample size and abundant information about confounding factors favors the inverse probability of censoring weighting model. When crossover is very infrequent, methods yield similar results. CONCLUSIONS Failure to correct for crossover may lead to suboptimal decisions by pricing and reimbursement authorities, thereby limiting an effective drugs potential.