Second-line strategies for metastatic renal cell carcinoma: classics and novel approaches

Abstract

Objectives: Renal cell carcinoma is an aggressive malignancy with a high propensity for both early and metachronous regional and distant metastasis. While surgical resection is the mainstay of therapy for patients with localized disease, the prognosis for patients with distant metastasis is poor with a 5-year survival rate of less than 10%. Response rates to first-line immunotherapy or immunochemotherapy range from 10-35%; responses achieved are predominantly partial remissions of short duration. Until today, there is no standard therapeutic procedure for the growing number of patients who relapse following first-line therapy and desire further active treatment.

Materials and methods: This article reviews classic and recent publications about second- and third-line approaches, their potential efficacy and toxicity.

Results: Several novel approaches have raised well-founded hope. Especially the application of monoclonal antibodies targeting VEGF signalling as well as different receptor tyrosine kinase inhibitors have the potential to change the face of second-line treatment of patients with metastatic RCC. Both groups of agents are focused in current phase III trials, either as mono- and/or combination therapy.

Conclusions: Until today, second-line treatment of patients with metastatic RCC progressing under therapy with biological response modifiers remains an unresolved issue. The results of ongoing clinical trials evaluating novel targeted approaches can be expected with suspense.

Fig. 1

Specific targeting of VEGF receptor signalling. Binding of VEGF to its receptor leads to dimerization and autophosphorylation of the intracellular receptor tyrosine kinases. Subsequently, several downstream protein pathways are activated, leading to biologic effects on endothelial cells [only the major proteins in each pathway are depicted (Cross et al. ; Rini and Small 2005)]. Motexafin gadolinium inhibits thioredoxin reductase which is implicated in activation of hypoxia-inducible factor-1α. Hsp90 blockers inhibit the proper folding of HIF-1α protein. Bevacizumab binds VEGF protein, preventing its interaction with the receptor. Thalidomide is supposed to reduce transcription of VEGF. AE-941 may compete with VEGF for binding with VEGFR-2. SU011248, AG-013736, PTK787, and BAY 43-9006 inhibit phosphorylation of the VEGF receptor. BAY 43-9006 additionally inhibits Raf-kinase enzyme. CCI-779 inhibits mTOR and therefore cell cycle progression, cell proliferation, survival and mobility, and—in addition—HIF-1α protein translation. Abbreviations: Akt/PKB protein kinase B, DAG 1,2-diacylglycerol, eNOS endothelial nitric oxide synthase, Erk extracellular receptor kinase, FAK focal adhesion kinase, FKBP12 FK-binding protein 12, HIF hypoxia-inducible factor, HSP heat-shock protein, MAPKAP 2/3 MAPK-activating protein kinase-2 and 3, MEK mitogen and extracellular kinase, mTOR mammalian target of rapamycin, p38MAPK p38 mitogen-activated protein kinase, PKC protein kinase C, PLC phospholipase C, SPK sphingosine kinase, PI3K phosphoinositide 3-kinase, VEGF vascular endothelial growth factor, VEGFR VEGF receptor