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

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Summary

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 world’s 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; $107–$556 million (2006 USD) in the US and $446 million–$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.

Introduction

Renal cell carcinoma (RCC) accounts for approximately 3% of adult malignancies and 90–95% of kidney neoplasms.1, 2, 3, 4, 5 In 2006, there were approximately 209,000 new cases and 102,000 deaths from RCC worldwide, including 39,000 new cases and 13,000 deaths in the United States (US).1, 5, 6, 7 Compared with other cancers, RCC remains relatively rare, but worldwide incidence and mortality rates are reported to be steadily rising at a rate of approximately 2–3% per decade.5, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17

The etiology of RCC is still largely unknown.13 In addition to obesity and hypertension, known risk factors for RCC include cigarette smoking, diet, diabetes, male gender (RCC is twice as common in men as in women) and, among women, oophorectomy and parity.13, 18 Occupational exposures to petroleum products, heavy metals, solvents, coke-oven emissions, or asbestos are believed to be contributors, but no definite carcinogens have been identified.13 Other environmental, genetic, and hormonal factors have been studied, but without definitive conclusion. The disease primarily afflicts men and women in the fifth and sixth decades of life.2, 13, 14 Characterized by a lack of early warning signs and diverse clinical manifestations, RCC has historically been a difficult malignancy to diagnose and treat. Because it remains clinically occult for most of its course, RCC is often diagnosed in advanced stages, usually by incidental radiologic study. About 25–30% of patients have metastatic disease at diagnosis, and fewer than 5% have solitary metastasis.2, 4, 19, 20, 21 Frequent sites for metastasis include the lung parenchyma (in 50–60% of patients with metastases), bone (in 30–40%), liver (in 30–40%), and brain (in 5%).4 However, virtually any organ site can be involved. With prognosis related directly to the stage or degree of tumor dissemination, mRCC generally results in extremely poor outcomes, with response rates for treated patients remaining at about 15–25%, survival ⩾5 years ranging from 5% to 10%, and overall median survival of less than one year.2, 4, 20, 22, 23, 24 The US National Cancer Institute has estimated that approximately 192,800 years of life were lost due to cancers of the kidney and renal pelvis in 2004, reflecting a per-person-dying average of 15.7 years of life lost.25 By comparison, per-person-dying years of life lost averaged 19.1, 15.1, and 14.0 years, respectively, for female breast, lung and bronchial and colorectal cancers.

MRCC is one of the most treatment-resistant malignancies. Cytoreductive surgery (i.e., nephrectomy, metastectomy) and systemic treatment with cytotoxic chemotherapy typically have limited or no effectiveness.4, 19, 21, 22, 24, 26, 27, 28, 29 Immunotherapy drugs (i.e., cytokines, such as interleukin-2 and interferon-alfa [IFN-α]) have proven modestly effective at delaying tumor growth and disease progression against mRCC, and have been the first-line and mainstay course of treatment for mRCC for the past two decades.24, 26, 29, 30, 31, 32, 33 Nonetheless, response rates of patients treated with these agents are extremely low and dose-limiting toxicity is high.26, 31

Recently, less-toxic molecularly targeted therapies (MTTs) have been the subject of clinical trials of advanced RCC, including mRCC. For example, Bevacizumab (Avastin®; Genentech, San Francisco, CA, USA)34 has shown clinical activity in mRCC,35 though it is not approved for the treatment of RCC.34 The real major advance in mRCC treatment was the approval in the US and Europe of two MTTs, sorafenib (Nexavar®; Bayer Healthcare, Leverkusen, Germany)36 and sunitinib (SUTENT®; Pfizer Inc., New York, NY, USA).37 These compounds are receptor tyrosine kinase inhibitors and operate through multiple signaling pathways to produce dual-action antiproliferative and antiangiogenic effects – complete with better therapeutic benefits and tolerability over conventional chemotherapy.19, 21, 26, 29, 38, 39 While both sorafenib and sunitinib are currently approved by the US FDA for advanced RCC,36, 37 NCCN treatment guidelines specifically recommend them for first-line systemic therapy in patients with relapse or stage IV and medically or surgically unresectable RCC.5

The efficacy and safety of sorafenib was proven in a large phase 3 trial conducted in advanced RCC patients who had received one prior systemic therapy (n = 903), where it was shown to significantly double progression-free survival (PFS) versus placebo across all patient subsets (5.5 vs. 2.8 months, respectively; P < 0.01).40 Similarly, the efficacy and safety of sunitinib for mRCC were demonstrated in a prospectively planned interim analysis of an international, phase 3 randomized trial of patients with previously untreated mRCC (n = 750): sunitinib treatment resulted in a significantly longer PFS and higher objective response rate than IFN-α (11 vs. 5 months and 31% vs. 6%, respectively; P < 0.001).38

Future treatment strategies for mRCC will likely incorporate a combination of these and other MTTs in development, possibly in multi-drug regimens with other angiogenesis inhibitors (e.g., bevacizumab).20, 35, 39 Also, the FDA has approved Torisel (temsirolimus), a specific inhibitor of the mammalian target of rapamycin kinase, for the treatment of renal cell carcinoma. As compared with interferon-alfa, temsirolimus improved overall survival among patients with mRCC and a poor prognosis.41

RCC patients and mRCC patients in particular – represent an underserved pool in the realm of cancer treatment. As the world’s population ages and the prevalence of risk factors (obesity, hypertension) increases, the burden of mRCC is foreseen to increase significantly. With the shift in treatment of mRCC to novel therapies, such as MTTs like sorafenib and sunitinib, clinicians, payers, and other healthcare decision-makers must re-evaluate the optimal role for new treatments in the clinical pathway. A timely understanding of the epidemiologic, economic and HRQOL burdens of mRCC on individuals and society clearly is needed at this juncture. It is our intention in this paper to provide an overview of this burden as has been reported in published literature.

Section snippets

Methods

We performed a comprehensive literature search in MEDLINE for articles pertaining to the epidemiologic, economic, and health-related quality of life (HRQOL) burdens of mRCC using a broad list of relevant search terms. Top-level search terms included “renal cell carcinoma,” “renal carcinoma,” and “kidney cancer” combined with various search-narrowing descriptors, such as “metast,” “burden,” “epidemiol,” “incident,” “prevalen,” “econ,” “cost,” “quality of life,” “utility” and “HRQOL.”

Results

Studies addressing the epidemiologic and socioeconomic burden of mRCC are relatively sparse in the literature. The combined primary and secondary search strategies resulted in >200 abstracts that were subsequently screened by the reviewers. After detailed review of the selected articles’ full-text, only approximately 50 were determined to be relevant to the epidemiologic, economic, and HRQOL burdens of mRCC. These papers are discussed accordingly by these categories below.

HRQOL burden

Although incidence, prevalence, mortality, and economic costs have been the most frequently used indicators of disease burden, there is now widespread application of measures designed to assess the impact of cancer on HRQOL.60, 61, 62 In addition to the burden of mRCC at the societal level (as discussed above), mRCC and its treatment affects multiple dimensions of individual patients’ everyday lives and overall well-being. HRQOL is a multidimensional concept measured through subjective

Discussion and conclusions

An increasing incidence of RCC has been apparent in the US and other countries worldwide for several decades. As the population ages and the prevalence of RCC risk factors increases, the burden of metastatic disease is predicted to increase as well. As novel and more efficacious therapies for mRCC have been introduced to the market in recent years, important concerns are now emerging about their impact and the impact of the disease itself on the epidemiologic, HRQOL, and economic burdens of the

Conflict of interest statement

Pfizer Inc. provided financial support to conduct this research. We declare no conflict of interest in relation to this paper.

Acknowledgements

This study was funded by Pfizer Inc. The authors would like to thank John Caloyeras, Jamie Banks, Yoko Komatsuzaki, and Sanjeev Balu from Abt Associates Inc. for their contributions to our study.

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