\title{Cost-Effectiveness Analysis of Sunitinib versus Interferon-Alfa for First-Line Treatment of Advanced and/or Metastatic Renal Cell Carcinoma in Singapore}

\author{Sil-ling Pruis, Mohamed Ismail Abdul Aziz, Fiona Pearce, Min Han Tan, David Bin-Chia Wu, and Kwong Ng}

\begin{abstract}
Objectives. This study was conducted to evaluate the cost-effectiveness of sunitinib versus interferon-alfa for the treatment of advanced and/or metastatic renal cell carcinoma (RCC) in Singapore.

Methods. A partitioned survival model with three health states (progression-free, progressive disease, and death) was developed from a healthcare payer perspective over a 10-year time horizon. Survival curves from the pivotal trial of sunitinib versus interferon-alfa were extrapolated beyond the trial period to estimate the underlying progression-free survival and overall survival parametric distributions. Health state utilities were derived from the literature and direct costs were sourced from local public healthcare institutions. The sunitinib dose in the model reflected local prescribing practices whereby a combination of 50 mg (28 percent) and 37.5 mg (72 percent) strengths are used.

Results. The base-case analysis comparing sunitinib versus interferon-alfa resulted in an incremental cost effectiveness ratio (ICER) of SGD191,061 (USD139,757) per quality-adjusted life-year gained. Sensitivity analysis demonstrated that the ICER was most sensitive to variations in the utility value assumed for the progression-free health state and the price of sunitinib.

Conclusions. In the absence of any price reduction, sunitinib had an exceedingly high ICER and was not considered a cost-effective use of healthcare resources in Singapore’s context for the first-line treatment of advanced RCC. The findings from our evaluation will be useful to inform local healthcare decision making and resource allocations for tyrosine kinase inhibitors when appraised alongside comparative clinical effectiveness data and payer affordability considerations.
\end{abstract}

\section{Introduction}
Renal cell carcinoma (RCC), also called renal adenocarcinoma or hypernephroma, is a cancer originating in the lining of the tubules of the kidney. It accounts for approximately 85 percent of renal cancers and 3 percent of all adult cancers globally. Clear cell RCC is the most common sub-type of RCC, accounting for approximately 80 percent of renal cancers \cite{1}.

Local clinical experts estimate that up to 160 new cases of advanced and/or metastatic RCC are diagnosed annually in Singapore. While there is substantial heterogeneity among these patients, their prognosis is typically poor. The American Cancer Society reported a 5-year survival rate of 8 percent for patients with tumor, node, and metastasis (TNM) stage IV disease at diagnosis \cite{2}.

Interferon-alfa has been superseded by tyrosine kinase inhibitors (TKIs), sunitinib and pazopanib, in recent years as first-line pharmacological standard of care for patients with advanced and/or metastatic RCC in Singapore \cite{3}. However, the cost of these treatments is high and can be unaffordable for patients with low incomes. In the public healthcare sector, government subsidies are provided to eligible patients for drugs which are considered cost-effective and fill an unmet clinical need, following a formal technology evaluation and deliberation of the evidence by a national committee. To the best of our knowledge, there are no published economic evaluations of TKIs for advanced and/or metastatic RCC in Singapore. Therefore, this study was conducted to evaluate the cost-effectiveness of sunitinib versus interferon-alfa with a view to inform local drug subsidy decisions for TKIs.

\section{Methods}

\subsection{Clinical Effectiveness}
A systematic literature search was conducted in PUBMED (Medline) and Embase electronic databases to identify all relevant studies published up until August 2017 which compared