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Renal cell carcinoma – cancer therapy in the flux About 3 % of cancer diseases are renal cell carcinomas, diagnosed mostly at the age between 60. and 70. The highest incidence rate can be documented in highly developed industrialized countries. In the last years a 2 % increase could be observed within Europe. More men than women fall ill with renal cell carcinomas (proportion: 1,5:1) Etiological risk factors are smoking, overweight and antihypertensive therapy By using new technologies in imaging such as ultra sound an CT so called incidental carcinomas can be diagnosed, characterized by small size and lower tumor stage. A so called stage immigration of renal cell carcinoma could be observed within the last years. Hence more T1 tumors and less high tumor stages (T2 – 4) are found. Diagnosis Today more than 50% of renal cell carcinomas are detected randomly by using ultra sound and CT. Using contrast enhanced computed tomography or if necessary MRT, the primary tumor size, participation of Vena Cava, growth of lymph nodes or an possible participation of adrenal gland and liver are determined preoperatively. This is essential for planning a surgical restoring. Also very important, the function assessment and morphology of the contralateral, healthy kidney. Prognostic Factors for Patients suffering from Renal Cell Carcinoma Survival of patients with renal cell carcinoma depends on: 1. 2. 3. 4. 5. TNM stage (tumor size, involvement of lymph nodes, metastases) Histological cell type (clear cell, papillary, chromophobe) Fuhrmann degree Vascular invasion Performance status Currently there is no molecular prognostic marker available for clinical routines. In future, following markers could be important for prognosis and therapy planning for patients 1/9 Renal cell carcinoma – cancer therapy in the flux with renal cell carcinoma: Carboanhydrase IX Expression 1. 2. 3. 4. 5. 6. 7. Vascular Endothelial Growth Factor Expression (VEGF) Hypoxia Inducible Factor (HIF) KI 67 (Proliferation Marker) P53 (Anti Oncogenic) CD44 (Cell Adhesion Molecule) E-Cadherine (Cell Adhesion Molecule) PTEN (Cell Cycle Regulator) Therapy of organ-confined tumors Since years Tumor Nephrectomy is the gold-standard for curative treatment of organ-confined renal tumors. Renal tumors with less than 4 cm in diameter should be nowadays operated without removing the organ (“nephron sparing”) because - compared with radical nephrectomy - comparable long-term survival and recurrence rates are shown. Within the last years laparoscopic techniques became also an established method in treating renal tumors, where little, peripherally located renal tumors an ideal indication for this technique. Current available data shows – referring to tumor-specific survival rates – similar results with open or laparoscopic tumor nephrectomy. The laparoscopic method shows less morbidity compared to the open technique. This is also valid for the laparoscopic excision of renal tumors. Long-term experiences of the oncological outcome are still pending. 2/9 Renal cell carcinoma – cancer therapy in the flux Patients for whom an operation is not reasonable have alternatives in Radio Frequency Ablation or Cryotherapy. However, this minimal invasive methods count still as experimental until today. However there has been a significant change in the area of systemic tumor therapy on metastatic renal cell cancer. Renal cell cancer rate as chemo-resistant Additionally to surgery especially immunotherapy with cytokines was available over many years. Tumor Nephrectomy on patients with metastatic renal cancer is a palliative therapy approach and is a cytoreductive therapy. An additional systematic therapy is necessary. A combined Tumor-Nephrectomy with Immunotherapy (Interferon α) shows in two clinical randomized trials better long-term survival than Immunotherapy without Nephrectomy. Complete resection of metastases improves the clinical prognosis, whereas only Immunotherapy does not. Especially when treating patients with metastatic clear cell renal cell carcinoma important progress has been made. New oral available receptor Tyrosin Kinase Inhibitors such as Sunitinib and Sorafenib, the vascular endothelial growth factor (VEGF) receptor binding anti-body Bevacizumab and the mTOR Inhobitors Temsirolimus and Everolimus, have replaced the conventional Immunotherapy. 3/9 Renal cell carcinoma – cancer therapy in the flux Antiangiogenic Therapy with Sunitinib, Sorafenib and Bevacizumab By deactivation of the Van Hippel Lindau Gene on chromosome 3p an accumulation of Heat Inducible Factor (HIF) in sporadic renal cell carcinoma occurs. Activating HIF leads to building of vessel endothelial growth factor (VEGF) and platelet derived growth factor (PDGF). These two growth factors play a key-role in vascularization, which are the basic requirement for metastatic spread and progress of renal cell carcinoma. The in renal cell carcinoma effective tyrosine kinase inhibitor Sunitinib (Sudent) and Sorafenib (Nexavar) are new targeting approaches of modern cancer therapies that restrains the tumor growth. Sunitinib and Sorafenib block the tyrosine kinase of different receptors and thus intervene with the intracellular signal transduction of tumor growth factors such as VEGF. A randomized phase 3 trial with Sunitinib showed a significant prolongation of the progress free interval from 5 to 11 month compared with the Interferon therapy. (Increase of medial overall survival from 21.8 to 26.4 month [Motzer et al NJM 2007]. Two Multicenter phase 2 trials with Sunitinib as second line monotherapy showed on 30-40% of the treated patients a partly response rate, 27-29% reached a stabilization of the disease for at least three month [Motzer JCO 2006]. 4/9 Renal cell carcinoma – cancer therapy in the flux Sunitinib is allowed as a first line therapy on patients with low or medium risk. Complete remissions of metastases in the brain – after a 12 week treatment with Sunitinib – have been stated. That shows a good penetration of the blood-brain-barrier. Good response rates have also been reported on lung metastases and local relapse after Tumor Nephrectomy [Medione et al Ann Oncol 2007] Side effects of Sunitinib are fatigue, diarrhea, nausea, vomiting, hand-foot syndrome, hypertension and hyopthyreoidismus. Sorafenib is an oral multikinase inhibitor. A phase 3 trial that compared Sorafenib with a placebo after failing of systemic Immunotherapy showed an advantage of progression free survival of 3 month in Sorafenibarm [Escudier B N Engl J Med 2007]. On primarily randomized patients Sorafenib showed – compared with Interferon – no statistically significant difference referring to the medial progression free survival. Sorafenib has been successfully used after progression under Interferon therapy. Disease stabilization and a medial progression free survival of 5.3 month have been achieved. On untreated patients Sorafenib showed a medial progression free survival of 9 month [Ryan CW JCO 2007] as well as the passage of the blood-brain barrier and a stabilization of brain metastases. As most often side effect fatigue and hand-foot syndrome have been reported. Sorafenib is recommended as second line therapy on patients with metastasized renal cell carcinoma. Bevacizumab plus Interfenon α 5/9 Renal cell carcinoma – cancer therapy in the flux The anti-body Bevacizumab is effective in metastasized renal cell carcinoma by binding directly on the VEGF receptor and blocking its biological activity. Bevacizumab must be given with Interferon α. Studies with Bevacizumab as single substance showed no significant success on patients with metastasized renal cell carcinoma. Two phase 3 trials showed good success rates with Bevacizumab and Interferon as first line therapy. The combination therapy gave better results on medial progression free survival compared with solely Interferon therapy by approximately 3 month difference in progression free survival. Side effects add up through necessary simultaneously use of both substances. The most common are hypertension, anorexia, fatigue and proteinuria. Central Switch-Point to simulate tumor growth: The mTOR-signal flow The therapies already mentioned improved progression free survival, but - if they fail - lack the possibility to treat further on a high level of evidence. A hyper active signal flow of cancer cells comes from the serine/threonine kinase, synonymous with mTOR (mammalian target of Rapamycin). mTOR can be looked at as a neoplastic switch that is activated through many oncological mutations. This enzyme refreshes in turn proteins, which regulate cell growth, cell cycles, programmed cell death, DNA replication and cell division. Tumor cells react very sensitive to mTOR-inhibition. The mTOR blockade leads to suppression of cell growth, proliferation, metabolism and angiogenesis in tumor cells. mTOR inhibitors like Temsirolimus and Everolimus show for the first time promising results in phase 3 trials and significantly extend the disease-free survival 6/9 Renal cell carcinoma – cancer therapy in the flux In Europe Temsirolimus is recommended as a first line therapy for patients with poor prognosis. In a phase 3 trial, which compared Interferon therapy with Temsirolimus, showed a significant longer overall survival on patients that have been treated with Temsirolimus (10.9 month) against Interferon (7.3 Month) or combination therapy (8.4 month). Also the medial progression free survival was significantly prolonged on patients treated with Temisirolimus (5.5 versus 3.1 month [Hudes G N Engl J Med 2007]). Even a complete remission of metastases among advanced cytokine refractory carcinoma has been stated in a phase 2 trial. A phase 3 trial ARCC (A global Trial for Advanced Renal Cell Carcinoma) for advanced renal cell cancer showed that Temsirolimus can extend the overall survival up to 49% versus the common standard therapy with Interferon α. It showed that all patient benefit from a therapy with Temsirolimus – regardless of a previous tumor nephrectomy (Hess G et al. J Clin Oncol 2008). Temsirolimus is well tolerated; side effects are edema, stomatitis, hyperglycaemia , hypercholesteraemia, hyperlipidemia. Everolimus If the treatment with Sunitinib, Sorafenib or Bevacizumab and Interferon is failing, Erverolimus is recommended as a second line therapy. Everolimus specifically blocks the mTOR. In this way the active agent stops the effect of VEGF and other vascular-growth factors, especially during hypoxia, a strong growth stimulus. The substance is given orally, which is different to Temsirolimus , another mTOR-inhibitor. The clinical effect of Everolimus has been tested in a phase 3 trial (RECORD-1) on patients, who no longer respond to VEGF and tyrosine kinase blockers. The tumors belonged to all three risk-groups (small risk about 29%, medium risk about 56%, and high risk about 14%). 7/9 Renal cell carcinoma – cancer therapy in the flux The time span while the tumor growth was stopped has been prolonged more than two times compared to a placebo (1.87 to 4.9 month). Side effects were stomatitis, infectious and non-infectious pneumonitis. The hand-foot syndrome, a typical side effect of tyrosine kinase inhibitors, was not occurring under Everolimus. Everolimus brings next to the oral application, its beneficial side effect profile and also due to the significantly progression free survival, advantages for the patients. Hopeful future for patients with metastasized renal-cell-carcinoma Therapy of metastasized Renal-Cell-Carcinoma is currently under continuous change. Numerous promising VEGF “Receptor-Targeted-Agents” like Axitinib and Pazopanib are under development. With Axitinib, currently in phase 3 trials, a medial overall survival up to 32 month has been reported. Pazopanib prolonged the progression free survival versus placebo from 4.2 to 9.2 month. Due to these new therapy-modalities the overall survival can be significantly prolonged when comparing the current survival-time with those from zytokinera, which was less than 15 month. Modern “Smart-Drugs” and “Targeted Therapies” will in future expand the oncological arsenal, not only on advanced renal cell carcinoma. Summery Today Sunitinib (Sudent) is recommended as first line therapy on metastasized renal cell carcinoma with small and medium risk. As an alternative - Bevacizumab (Avastin) with IFN α can be given. 8/9 Renal cell carcinoma – cancer therapy in the flux Patients with poor prognosis should receive Temsirolimus as a first line therapy. Sunitinib counts as alternative. As a second line therapy for those patients is Sorafenib recommended. Up-to-date treatment recommendation for patients with metastasized renal cell carcinoma - MSKCC risk groups First line, second line Favorable risk – Sunitinib Bevacizumab + IFN α IL-2 and Interferon on selected patients Sorafenib Sunitinib mTOR inhibitors Intermediate risk – Sunitinib Bevacizumab + IFN α Sorafenib on selected patients Sorabenib mTOR ihibitors Poor risk – Temsirolimus Sunidtinib Sorafenib Resource (BJU Int.2009 Jul; 104[1]:10-8.) 9/9