Advances in understanding the molecular biology and genetics variants of malignancies have led to novel targeted approaches for the treatment of advanced or metastatic genitourinary tract cancers. Targeted therapies are drugs or substances that block the growth and spread of cancer by interfering with specific molecules involved in tumor growth and progression. By focusing on molecular and cellular changes that are specific to cancer, targeted therapies are theoretically be more effective than the systemic chemotherapy or radiotherapy and less harmful to normal cells, thus reduce side effects and improve quality of life. Many of these therapies focus on proteins that are involved in cell signaling pathways. The majority of recent advancement in the genitourinary tract field is focusing on kidney cancer.
The predominant cell type of kidney cancers is clear-cell renal cell carcinoma (ccRCC), comprising more than 85% of metastatic RCC. The basic biology underlying the development of ccRCC is critically dependent on the von Hippel-Lindau gene (VHL). Aberrations in VHL’s function lead to accumulation of the transcriptional regulatory molecule, hypoxia inducible factor alpha (HIFα). HIFα can then upregulate a series of hypoxia-responsive genes, including vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and others. Overexpression of HIFα is also related to stimulation of receptor mammalian target of rapamycin (mTOR). Both the VEGF and the mTOR pathways provide opportunities for the development of molecularly targeted drugs in RCC. Currently, target the elevated VEGF either by humanized monoclonal antibody to VEGF (Bevacizumab) or to inhibit downstream signaling to VEGFRs by the multitargeted tyrosine kinase inhibitors (Sunitinib, Sorafenib, Pazopanib, Axitinib) are approved as first- or second-line targeted therapeutic agents by FDA and are ready to use in Taiwan. In addition, to target HIFα’s starting levels PI3K/Akt/mTOR pathway which results in inhibiting mTOR’s kinase activity and lead to cell cycle arrest, two (temsirolimus and everolimus) that now have level I evidence supporting their use in the setting of ccRCC are also available in Taiwan. In the clinical trial and/or in official practice, these agents have shown promising results in inhibiting tumor angiogenesis that demonstrated a prolong progression free survival (PFS) compared to interferon-α or placebo, with manageable adverse events (AEs). Clearly, molecular targeted therapies have better efficacy and tolerability than cytokine therapy, and many are administered orally. However, although PFS has become a popular primary endpoint and has served as the basis of approval for several targeted therapies, durable complete responses remain elusive and the overall survival benefit do not reach in the most trials observed. Given the inherent but unmet complications of a required long duration of follow-up that is impossible for those terminal ill mRCC patients, and a required large population to be analyze, and confounding caused by crossover trial designs or effects of subsequent therapy after disease progression on the agent of interest. This obstacle has yet to wait for solve. Nevertheless, targeted therapies still have some limitations. Among these, the most troublesome is the potential for cancer cells to develop resistance to the agent used. The other challenges remain to be faced: How to select the best first-line or subsequent therapy for a given patient? The optimal sequencing of the various agents available, designing trials with appropriate comparison arms and endpoints, and Identifying safe and effective drug in combinations are warranted for further investigations. Similarly, efforts to decipher the molecular mechanisms underlying non-clear cell variants of RCC are beginning to engender novel therapeutic strategies directed against these rarer forms of kidney cancer.
Regarding the prognostic prediction of target therapeutic treatment, some of the AEs (hypertension, hand- foot skin reaction, thrombocytopenia, hypothyroidism, and hypercholesterolemia, lactate dehydrogenase) are deemed to be the biomarkers for a more effectiveness of treatment outcome. The awareness and identification of these AEs and treat it accordingly may help to select a subset of patient population with better prognosis. The concept of neoadjuvant therapy is attractive; however, the approach must be validated in randomized clinical trials before being widely adopted. The role of cytoreductive nephrectomy in patients with mRCC receiving VEGF targeted therapy is deserved for further approves. The efficacy and tolerability of targeted therapies in the elderly are generally similar to those observed in their younger counterparts. In conclusion, despite the greatly advanced in molecular targeting the onco-pathways related which led to a remarkable improvement in PFS, the heterogeneity of cancer tissues and the alternative pathways encountered treatment failure as well as the development of subsequent drug resistance are outline the future research direction to combat the disease processes. As more information regarding mechanisms of disease and drug resistance becomes available, new targets, new targeted agents, and new combinations will provide maximal efficacy with manageable toxicity. At this moment, the treatment of advanced RCC continues to be a major challenge for uro-oncologists.