Download Renal cell carcinoma – cancer therapy in the flux

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:
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2.
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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
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with renal cell carcinoma:
Carboanhydrase IX Expression
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2.
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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.
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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.
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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].
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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
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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
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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%).
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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.
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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
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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.)
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