New treatment modalities for RCC

European Association of UrologyApr 21 2010

Renal cell carcinoma (RCC) accounts for about 3% of all solid tumours in adults, and worldwide, more than 200.000 new cases and 100.000 deaths result each year from this malignancy.

"In contrast to most other malignant tumours in the urogenital system, there was a period of stagnation in the development of new treatment modalities for many decades. Surgery in an early stage always was and still is the only measure to cure RCC, and surgery plays an important role in the treatment of metastases as long as they can be removed completely," said Prof. G-nter Janetschek, one of the speakers at the Plenary Session, Advances in Renal Cell Carcinoma Management.

He added that in contrast, the main targets for other malignancies - chemotherapy and radiotherapy - failed to a great extent, and immunotherapy proved to have limited efficacy despite many efforts.

Frequently, the so far standard surgical treatment - radical nephrectomy - is an overtreatment for these small tumours, and in addition to partial nephrectomy - open or laparoscopic - minimally invasive ablative techniques, namely cryotherapy and radiofrequency, have become an important addition to the range of options available.

Janetschek said a major breakthrough could be achieved in the treatment of advanced disease due to better understanding of tumour biology in general and especially RCC biology. Angiogenesis plays a major role in the growth of malignant tumours, and several substances could be developed to block key proteins involved in angiogenesis and tumour proliferation.

The main strategies target either directly the vascular endothelial growth factor (VEGF), its related receptor or the mammalian target of rapamycin (mTOR) signal transduction pathway.

"Since all of these concepts are new, only limited experience exists so far with their clinical use. However, this experience is growing quickly with each year. Therefore, continuous close communication between all groups working in this field is of outmost importance at this stage," said Janetschek.

VEGF is the most prominent regulator of angiogenesis. Bevacizumab is a monoclonal antibody against VEGF that binds and neutralises all biologic active isoformes of VEGF. Bevacizumab is one of the drugs used as first-line therapy, and there is consensus that the combination of bevacizumab and interferon-alpha is most efficient.

Sunitinib is a highly potent selective inhibitor of multiple tyrosine kinases of the VEGF and PDGF (platelet derived growth factor) receptors. In addition to inhibition of angiogenesis it has direct antiproliferative effects. Sunitinib is recommended as first-line therapy for intermediate- or low-risk patients. Many studies have shown its efficacy.

Sorafenib is a tyrosine kinase inhibitor which inhibits not only the VEGF/PDGF receptors, but also the enzyme RAF (rapidly growing fibrosarcoma) kinase, a critical component of the RAF signaling pathway that controls cell division and proliferation. Sorafenib is advised as second-line therapy. Treatment of cytokine-refractory mRCC patients with sorafenib has been reported to double the progression free survival (PFS) compared with placebo.

Initially, mTOR inhibitors were used as an immunosuppressant to prevent rejection of organ transplants. Temsirolimus is a specific inhibitor of mTOR and interferes with the synthesis of proteins that regulate proliferation, growth, and survival of tumour cells. Treatment with temsirolimus leads to cell cycle arrest in the G1 phase, and also inhibits tumour angiogenesis by reducing synthesis of VEGF.

Temsirolimus is indicated as first-line therapy in high risk patients. It is administered intravenously. Everolimus, which is given orally, has shown in a phase III study to be effective in patients relapsing after initial therapy with tyrosine kinase inhibitors.

None of these drugs cure the patients, but they are able to stabilise mRCC for a certain period of time. Many questions remain open, however. Obviously, there is no cross-resistance in between these drugs, and they can be administered sequentially.

Janetschek said that specialists have to define which the best sequence is in the given patient. Another new approach is the combination of drugs. This approach will result in new side effects which, according to Janetschek urologists have to recognise and manage.