Systemic Therapy

Historical Therapies

Standard cytotoxic chemotherapy agents have been shown in multiple studies to be ineffective therapies for renal cell carcinoma. Two initially promising treatments included:

  • Inteferonalpha
  • Interleukin-2 (IL2)

Modern Therapy

Multiple clear cell carcinomas occur in patients with Von Hippel Lindau syndrome. This led to further understanding of the biology of clear cell carcinomas once the VHL gene was identified. The VHL gene product binds to HIF-1𝜶 protein in the presence of oxygen, preventing HIF-alpha from moving to the nucleus and functioning as a transcription factor. HIF-1𝜶 is involved in multiple cell cycle pathways. Renal cell carcinomas were then identified to possess mutations in the VHL gene which led to unrestricted activity of HIF-1𝜶. Important signalling molecules which are upregulated by HIF-1𝜶 include Vascular Endothelial Growth Factor and Platelet Derived Growth Factor (VEGF/PDGF). This has led the use of targeting these pathways - bevacizumab which binds to the VEGF molecule, and sunitinib/sorafenib (and otherws) act on the VEGF-receptor to prevent the activation of downstream signalling cascade.

Further exploration of factors influencing the expression of HIF-1𝜶 led to identification of other factors which can lead to its overexpression. One of the first successful targets identified was the mTOR protein.

VEGF Receptor Inhibitors

The Motzer et al trial demonstrated a doubling in median survival and a 31% response rate (compared to a 6% response rate for interferon-𝜶). It was published in 2007 and led to a major shift in the treatment of renal cell carcinomas. Overall survival was on the margin of significance but this is likely due to crossover allowed in the trial.
Sorafenib was studied by Escudier. Although the difference in survival was not significant, there was an improvement in progression free survival.
Side effects of VEGF Receptor Tyrosine Kinase Inhibitors include fatigue, nausea, vomiting, hypothyroidism and hypertension. Hypertension appears to indicate a good response to therapy.
Newer VEGF Receptor Inhibitors include axitinib (potentially more potent) and pazopanib.

VEGF Inhibitors

Escudier also published a trial in 2007 which demonstrated superiority of bevacizumab + interferon over interferon alone. The combination of bevazicumab with interferon in the investigative arm has meant the role of bevacizumab alone has never been explored (and is unlikely to).

mTOR Inhibitors

Temsirolimus was compared in a study by Hudes et al with interferon alone and together with interferon. The temsirolimus-alone arm performed better than the combination arm and the interferon alone arm. Temsirolimus was shown to be most effective in high risk disease.
Everolimus was evaluated as second line treatment compared to placebo. Progression was significantly delayed (from 2 to 5 months). Everolimus is now established as a the first choice for second line treatment.
Side effects include fatigue, sore mouth, skin effects, hyperlipidaemia, and rarely pneumonitis.

Summary

First line therapy should be sunitinib or pazopanib unless patients have poor-prognosis disease, in which case temsirolimus is used. Interleukin-2 has a significant benefit in a very small, difficult to identify group. Subsequent therapy should be everolimus


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