Renal cell cancer and new treatment modalities
Uitgegeven: 03-01-2007
 | Dr. Th.M. de Reijke Uroloog Academisch Medisch Centrum, Amsterdam |
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The incidence of renal cell cancer is increasing not only due to the earlier detection because more ultrasound investigations are performed in case of undetermined abdominal complaints. Renal cell cancer accounts for 3% of malignant diseases in the male and the tumour is diagnosed most frequently during the 5th to 6th decade. One third of the patients have already metastases at the time of diagnosis. Due to the more frequent application of ultrasonography, Ct-scan and MRI renal tumours are diagnosed at an earlier stage and in these cases the chance of cure is much better. There is a clear relation between stage and survival and once the lymph nodes are involved the 5 year survival rates drop from approximately 65% to 30%. But even in early stages the chance of cure after 5 to 10 years is only 70 to 50%. It is clear that improvement in the treatment of renal cell cancer is needed. When a patient is diagnosed with a localized tumour without signs of metastatic spread, radical surgery is the treatment of choice. The extent of surgery is not well defined, but in small tumours the general approach is to try to perform a nephron sparing technique even in the presence of a normal contra lateral kidney by the open or laparoscopic technique. Recently new minimal invasive techniques are being explored to treat small renal cell cancers, e.g. cryosurgery, radiofrequency, high intensity frequent ultrasound. In case of more advanced disease the extent of surgery is not clearly defined, but a lymph node dissection is probably not of any additional benefit in case the lymph nodes are macroscopically normal, the same holds true for the resection of the ipsilateral adrenal gland. In case of the subsequent development of respectable metastases, surgical resection offers the best results, especially in case of soft tissue metastatic lesions and long-term survivors have been described with 20-40% 5-year survival rates. In case of concomitant metastatic disease it has recently been shown in a European and American randomized trial that radical nephrectomy in combination with immunotherapy results in improved survival rates compared to immunotherapy alone. Immunotherapy is the only effective therapy in advanced renal cell cancer, chemotherapy and radiotherapy have been shown to be ineffective. Non-specific immunotherapy, using interleukins or interferon alone or in combination has been shown to be moderately effective, response rates 5 to 15%. Specific immunotherapy using dendritic cells, monoclonal antibodies and gene therapy are under investigation, but response rates are still moderate. For cancer cells angiogenesis is an essential prerequisite for further growth and cell spread. Renal cell cancers are in most cases highly vascularised tumours. In renal cell cancers mutations are found in the Von Hippel Lindau tumour suppressor gene in approximately 70% of cases. In case of a loss of the Von Hippel Lindau protein function a hypoxia inducible factor is activated and also hypoxia inducible genes, e.g. VEGF, PDGF, TGF. Vascular endothelial growth factor A is a multifunctional cytokine widely expressed in tumour cells. It acts through VEGF receptors that are expressed on vascular endothelium and on some tumour cells. It is well established that VEGF-A is an important angiogenic cytokine with a critical role in tumour angiogenesis and progression through its binding to VEGFR’s. A new approach is the inhibition of the VEGF by antibodies (bevacizumab, an anti-VEGF monoclonal antibody) or small molecules (tyrosine kinase inhibitors) such as sorafenib and sunitinib. These agents not only block VEGFR tyrosine kinase, but also other receptors e.g. PDGFR and this blocking of receptors of the kinase domain superfamily of receptor tyrosine kinases is different for sorafenib and sunitinib. The activity of these two angiogenesis inhibitors was proven in Phase II trials as second line treatment of metastatic disease and later confirmed in Phase III trials in first and second line setting. In patients with renal cell cancer sorafenib was compared with placebo in patients that had failed interferon or interleukin therapy. Median progression-free survival was 24 weeks in the sorafenib group and 12 weeks in the placebo group, 74% of patients in the active treatment group showed some degree of tumour shrinkage. The oral treatment was well tolerated. Side effects were hypertension, diarrhoea, rash, hand/foot skin reaction, and neuropathy. Because this clear advantage for the sorafenib treated patients an independent data monitoring committee decided not to continue with the placebo arm and this has implications for the analysis of the primary endpoint of this trial (overall survival). Since this trial showed beneficial results in second line treatment (better than with interleukin and interferon) studies were initiated as first line treatment comparing this angiogenesis inhibitor with interferon. Since the chance for recurrence is high, especially in patients that underwent a radical nephrectomy where pathogical examination showed risk factors for relapse, these agents are also explored in an adjuvant setting. The SORCE trial (a joint MRC and EORTC study) will randomise these patients in a double blind fashion between sorafenib, placebo and sorafenib plus placebo. The possible problem will be the double blind fashion, because patients on sorafenib will experience side effects in a considerable number of cases. Another ongoing study will compare sunitinib, sorafenib and placebo. Of course, combination therapies have to be explored in patients with renal cell cancer, e.g. interferon, bevacizumab, inhibitors of TGF pathway (gefitinib, erlotinib) or mTOR inhibitors. Sorafenib and sunitinib are now registered for patients with renal cell cancer. Although these new agents are applied as an oral drug side effects are considerable and those who are treating these patients should be aware how to manage these side effects and when to decrease the dose. These agents are promising, but more data are needed for defining the optimal timing and combination. Laatste berichten van auteur(s)
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