© Borgis - Postępy Nauk Medycznych 2/2011, s. 146-149
Leczenie systemowe przerzutowego raka nerki. Przegląd piśmiennictwa
A systemic therapy of metastatic renal cancer. A review
Chemotherapy Department, Chair of Oncology, Medical University of Łódź, M. Kopernik Memorial Hospital
Head of Department: prof. dr hab. med. Piotr Potemski
Przez wiele lat przerzutowy rak nerki był uznawany za nowotwór oporny na chemioterapię. Jedynymi dwoma umiarkowanie aktywnymi lekami była interleukina 2 i interferon alfa ale korzyści z immunoterapii odnosili tylko nieliczni chorzy. W ostatnich latach postępy dokonane w poznawaniu biologii molekularnej raka nerki oraz opracowywanie związków ukierunkowanych molekularnie zwiększyły znacznie liczbę możliwych do zastosowania leków. Zarejestrowane są bewacyzumab, sunitynib, sorafenib, temsyrolimus, ewerolimus oraz pazopanib. Jednakże względnie duża liczba możliwości terapeutycznych może stanowić utrudnienie dla lekarza. Niniejsza praca jest przeglądem najważniejszych badań z użyciem nowych leków oraz próbą określenia, które ze strategii postępowania są najbardziej uzasadnione naukowo.
For many years metastatic renal cancer was considered as a chemotherapy-refractory disease. The only two modestly active agents were interleukin 2 and interferon alpha but very few patients benefited from immunotherapy. In recent years, the advances in molecular biology of renal cancer and development of targeted agents have expanded the therapeutic armamentarium. The approved drugs include bevacizumab, sunitinib, sorafenib, temsirolimus, everolimus, and pazopanib. However, relatively many options of possible treatment may sometimes confuse a physician. This paper is a review of the most important clinical trials with the new drugs and an attempt to define the most evidence-based treatment approaches.
In Poland in 2007 nearly 4 000 of new cases of renal neoplasm and 2 500 deaths caused by this disease were observed (1). According to EUROCARE-4, a 5-year survival rate of patients diagnosed with kidney neoplasm in 1995-1999 in 23 European countries was 58.0% (2). At that time in Poland it was 53.8% but only 6% of all new cases were covered. A renal cell carcinoma (RCC) comprises of 90% of kidney neoplasms. The most common histopathologic type of RCC is clear cell renal carcinoma (CCRC) and it represents about 80-90% of all RCC. The treatment of choice is radical surgery, but this method is limited to early stages.
For many years metastatic RCC was considered as a chemotherapy-refractory disease. The only two modestly active agents were interleukin 2 and interferon alpha but very few patients benefited from immunotherapy. Moreover, treatment with interleukin 2 was related to serious toxicity. Thus, the most widely used form of immunotherapy was the treatment with interferon alpha. In recent years, the advances in molecular biology of renal cancer and development of targeted agents have expanded the therapeutic armamentarium.
A crucial molecular event in molecular biology of renal cancer seems to be inactivation of von Hippel-Lindau (VHL) gene (3). A VHL protein is mandatory for the process of hypoxia-inducible factor 1 (HIF-1) regulation (4). In a normal cell, the alpha subunits of HIF-1 are degraded by the proteasome, whereas in a hypoxic cell they are stabilized. In the absence of VHL protein, alpha subunits of HIF-1 are constitutively stabilized despite the normal oxygenation. In such case, HIF-1 promotes angiogenesis and other typical cellular responses for hypoxia. In the majority of CCRC there is a loss of VHL gene function. The mechanisms of such suppression include: deletion of one or both alleles, gene inactivation by mutations (commonly observed in sporadic tumors) or promoter hypermethylation (3, 5).
The two most important molecular targets for new drugs in renal cancer are vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) pathways. HIF-1 induces expression of VEGF gene. VEGF protein is a potent proangiogenic factor that binds to its receptor on endothelial cells. mTOR is a cytoplasmic serine-threonine kinase that recognizes and mediates stress response signals from PI3K-AKT pathway. Its activation has been frequently observed in RCC (6). Several new agents targeting on VEGF or mTOR pathways have been developed. The approved drugs include bevacizumab, sunitinib, sorafenib, temsirolimus, everolimus, and pazopanib. Bevacizumab is a monoclonal antibody that binds to a VEGF protein. Sunitinib, sorafenib and pazopanib are small molecules that inhibit several protein kinases including tyrosine kinase of VEGF receptor. Temsirolimus and everolimus are mTOR inhibitors (7).
The possibility of having relatively many treatment options may sometimes confuse a physician. In this paper the most important clinical trials with the new drugs will be reviewed and the most evidence-based treatment approaches will be highlighted. These trials have been confined to patients with CCRC unless otherwise stated.
It has been demonstrated that interferon alpha prolongs both progression-free survival (PFS) and overall survival (OS) in patients with CCRC compared with medroxyprogesterone (8). There was a 28% reduction in a relative risk of death (p = 0.017) and an improvement in median survival by 2.5 months. However, very few patients really benefited from immunotherapy and such treatment was often related to significant toxicity, especially when high-doses of interleukin 2 were administered. As the survival gain for patients treated with interferon alpha was further confirmed in a meta-analysis, interferon alpha was regarded as a standard treatment of metastatic CCRC and a comparator in further clinical trials (9).
Some attempts have been made in order to identify possible predictive and prognostic factors in patients treated with interferon alpha. First of all, two prospective trials confirmed the role of nephrectomy. Cytoreductive nephrectomy prior to immunotherapy decreased a relative risk of death by 31% (p = 0.002) and prolonged median survival by 5.8 months (10). Motzer et al. proposed a prognostic model for patients treated with interferon alpha on prospective trials at the Memorial Sloan-Kettering Cancer Center (11). In this model five variables were included:
1. Poor Karnofsky performance status (≤ 70).
2. High serum lactate dehydrogenase level (> 1.5 x the upper limit of normal).
4. High corrected serum calcium (> 10 mg/dl).
5. Short time (< 12 months) from the initial diagnosis to the beginning of interferon treatment.
Three risk categories (known as MSKCC or Motzer?s risk categories) are presented in table 1.
Table 1. Risk categories in the prognostic model proposed by Motzer et al. at the Memorial Sloan-Kettering Cancer Center (11).
|Number of risk factors||Risk category||% of patients||Median PFS (months)||Median OS (months)|
There are some data indicating that only patients at favorable risk may benefit from interferon alpha therapy. Negrier et al. have demonstrated that in the intermediate risk category immunotherapy provided no survival benefit (12).
Bevacizumab with interferon alpha was compared with interferon alone in the first-line therapy in two phase III trials: AVOREN in Europe and CALGB 90206 in the North America (13, 14). Patients enrolled in these trials had CCRC, a prior nephrectomy, and a favorable or intermediate risk category. Bevacizumab combined with interferon delayed disease progression and produced higher response rate. However, both trials failed to meet their primary endpoint, the prolongation of OS (15, 16). No group of patients benefited from adding bevacizumab to interferon alpha. This disappointing result could not be explained by the possible effect of a second-line treatment as there were no significant differences between treatment arms in the usage of active post-protocol therapies (15).
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