Dr. med. Dirk Manski



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Treatment of Metastatic Renal Cell Carcinoma

Prognosis of Metastatic Renal Cell Carcinoma

Motzer developed accepted criteria for the prognosis of metastatic renal cell carcinoma, which are used for the stratification of pations within trials of immunotherapy or targeted therapy (Motzer et al, 2002). See Table Motzer criteria for adverse risk factors and survival of three risk groups.

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Prognosis of metastatic renal cell carcinoma under immunotherapy (Motzer et al, 2002):
Low risk (0 risk factors): median overall survival of 30 months.
Medium risk (1-2 risk factors): median overall survival of 14 months.
High risk (3 or more risk factors): median overall survival of 5 months
Adverse risk factor limit
Reduced Karnofsky Index <80%
Elevated LDH >1.5 times upper limit of normal
Low hemoglobin below lower limit of normal
Elevated corrected calcium above normal value
Time from nephrectomy to metastases formation below 1 year

Cytoreductive nephrectomy in patients with metastatic renal cell carcinoma:

Cytoreductive nephrectomy prolongs survival in patients before scheduled immunotherapy and leads to the palliation of local symptoms (Mikisch et al, 2001). Laparoscopic cytoreductive nephrectomy offers advantages due to shorter recovery time and faster begin of tumor treatment. Retrospective trials support the use of cytoreductive nephrectomy prior to treatment with inhibitors of signal transduction in patients with good or intermediate prognosis (see Motzer criteria) (Heng et al, 2014). The results of randomized trials are awaited for 2015. Cytoreductive nephrectomy is not indicated for patients with advanced Ductus Bellini carcinoma or sarcomatoid renal tumors.

Surgical treatment of Metastases:

The removal of solitary metastases is indicated if surgical feasible to control local symptoms and to improve survival. Some authors advocate in selected cases the surgical resection of multiple metastases or residual tumors after targeted therapy. The prognosis after removal of a solitary RCC metastasis is less favorable in patients in whom metastasis was already present at diagnosis. If the metastasis is detected during follow-up, the time interval between nephrectomy and the emergence of metastases is prognostic.

Targeted Therapy with Inhibitors of Signal Transduction:

Phase 3 studies showed encouraging results with inhibitors of signal transduction. This applies to trials for the first-line treatment of metastatic renal cell cancer (randomized to immunotherapy) and after failure of first-line treatment (randomized to placebo) (Motzer and Bukowski, 2006). Inhibitors of signal transduction generate stable disease, complete remission is rare. Favorable prognosic signs are metastases which stabilize or decrease in size and show signs of decreased perfusion in computed tomography.

Targeted molecular agents show a favorable side effect profile in comparison to immunotherapy. Once started, targeted therapy must be continued as long as possible (until progression or intolerable side effects). Sequential therapy of "smart drugs" is followed by a change to the next targeted molecular agents, see flowchart sequential therapy of metastatic renal cell carcinoma.


Sequential therapy of metastatic renal cell carcinoma with inhibitors of signal transduction, modified from the EAU-guidelines (Ljungberg et al, 2010).
(1) Risk stratification of prognosis, please see Table Motzer criteria.
flow chart for sequential therapy of metastatic renal cell cancer with inhibitors of signal transduction

Axitinib:

Axitinib is a potent inhibitor of VEGF receptor tyrosine kinase. Axitinib has been approved since 2012 in the U.S. for the second-line treatment after failure with cytokines or first-line treatment with targeted molecules. Axitinib increased progression-free survival (6.7 vs. 4.7 months compared to sorafenib) (Rini et al, 2011). Starting dosage is 5 mg 1-0-1, if toxicity is acceptable the dosage is increased to 10 mg 1-0-1. See also chapter pharmacology section Axitinib.

Bevacizumab:

Bevacizumab is a monoclonal antibody against VEGF and is approved for first-line treatment of metastatic renal cell carcinoma. In combination with interferon, bevacizumab shows an increase in progression-free survival of 10.2 vs. 5.4 months in comparison to interferon therapy alone (Escudier et al, 2007) (Motzer and Bukowski, 2006). See also chapter pharmacology section bevacizumab.

Everolimus:

Everolimus is an inhibitor of mTOR (mammalian target of rapamycin), a central molecule in the intracellular signal transduction of cell growth, angiogenesis, energy metabolism and apoptosis (Faivre et al, 2006). Everolimus is approved after failure of first-line therapy with inhibitors of signal transduction (Motzer et al, 2008). The dosage of everolimus is 10 mg po 1-0-0. See also chapter pharmacology section Everolimus.

Pazopanib:

Pazopanib is a tyrosine kinase inhibitor (VEGF receptor, PDGF receptor tyrosine kinase and c-kit) with approval for first-line treatment and second-line therapy after interferon therapy of metastasized renal cell carcinoma (Hutson et al, 2010). Dosage is 800 mg 1-0-0, if relevant side effects occur dosage is reduced. See also chapter pharmacology section pazopanib.

Sorafenib:

Sorafenib is an oral multi-kinase inhibitor, which engages in the intracellular signal transduction of cell growth and angiogenesis. Inhibited kinases include RAF kinase, VEGF receptor kinases, PDGF receptor kinase, KIT, and FLT-3 (Escudier et al, 2007a). The EAU guideline recommends sorafenib as second-line therapy after failure of immunotherapy. Dosage is 400 mg 1-0-1, with relevant side effects a dose reduction to 200 mg 1-0-1 is possible or treatment is paused. See also chapter pharmacology section sorafenib.

Sunitinib:

Sunitinib is an oral multi-kinase inhibitor, especially of tyrosine kinases like VEGF and PDGF receptor kinases. Randomized studies with sunitinib showed an improved progression-free survival of 11 vs. 5 months compared to immunotherapy with interferon (Motzer et al, 2007). Overall survival was not significant longer: 26 vs. 22 months. Sunitinib is currently the reference substance for the first-line treatment of metastatic renal cell carcinoma with favorable or intermediate risk profile. Dosage of sunitinib is 50 mg daily for 4 weeks followed by 2 weeks of treatment pause. A longer treatment pause or dose reduction to 37.5 mg daily is recommended if relevant side effects are noticed. See also chapter pharmacology section sunitinib.

Temsirolimus:

Temsirolimus is an inhibitor of mTOR (mammalian target of rapamycin), a central molecule in the intracellular signal transduction of cell growth, angiogenesis, energy metabolism and apoptosis (Faivre et al, 2006). In high-risk patients, temsirolimus increased survival compared to immunotherapy (10.9 vs. 7.3 months) (Hudes et al, 2007). The dosage of temsirolimus is 25 mg i.v. weekly. See also chapter pharmacology section sunitinib.

Immunotherapy of metastatic renal cell carcinoma:

Treatment with interferon-α in combination with interleukin-2 and 5-FU results in a partial remission in selected patients (up to . However, there are some randomized trials with far less effect and without any effect on survival (Negrier et al, 2007). Immunotherapy causes significant toxicity and costs. Toxicity may be reduced with interferon-α monotherapy, but the response rate is even lower (Mancuso and Sternberg, 2005). With the emergence of targeted therapy, immunotherapy (without Bevacizumab) is hardly used any more.

Chemotherapy of metastatic renal cell carcinoma:

The following chemotherapy regims have been tested with only moderate response: gemcitabine and 5-FU, gemcitabine in combination with immunotherapy. Actually, no chemotherapeutic regimen is accepted as a standard of care.

Palliative Treatment Options in Metastatic Renal Cell Carcinoma:

Painful bone metastases:

Pain management is standard care. Additional therapeutic options are irradiation, bisphosphonates (zolendronate) or surgical stabilization.

Hypercalcemia:

Hypercalcemia is treated with corticosteroids in higher-dose, forced diuresis, saline infusion and bisphosphonates.

Local pain or bleeding tumor:

Palliative nephrectomy or embolization.

Brain metastases:

Irradiation (e.g. Gamma knife).

Future prospects in the treatment of advanced renal cell carcinoma:

Numerous substances have been developed and are now tested in clinical trials (Kanesvaran et al, 2014).

Inhibitors of signal transduction:

Aflibercept, Cabozantinib, Tivanitinib, Cedirafenib, Vandetanib.

Immune checkpoint inhibitors:

The activation of immune checkpoint receptors inhibits the activity of the cellular immune reaction, the physiological function is to prevent autoimmune diseases. Different receptors have been identified: PD-1 receptor (PD for programmed death) or CTLA-4 (CTLA for cytotoxic T lymphocyte antigen) on T-lymphocytes with corresponding ligands as PD-L1. tumors use above mentioned pathways to induce immune tolerance. The monoclonal antibody Nivolumab (anti PD-1) is tested against Everolimus in a phase-III trial. Further substances with activity against advanced RCC: Ipilimumab (anti CTLA-4).

ACE inhibitors:

The prescription of ACE inhibitors increased the prognosis in a retrospective analysis of over 4000 patients (17 vs 26 month survival) (McKay et al, 2014). Patients with arterial hypertonus and advanced renal cell carcinoma should receive ACE inhibitors to control hypertension. Further studies should be awaited for patients without arterial hypertension.

Prognosis of renal cell carcinoma

Natural history of localized renal cell carcinoma:

Renal tumors show in average a growth of 3–5 mm per year. Many small tumors do not grow. Metastases from renal tumors smaller than 3–cm are rare.

Clinical stage and prognosis:

Please see tab. clinical stage and prognosis of renal cell carcinoma and tab. T stage and survival.

Grading and survival:

5 years survival rates depending of grading: G1 (89%), G2 (65%), G3 (46%).

Prognosis of renal cell carcinoma with lymph node metastasis:

5 years survival rate 5–30%.

Prognosis of renal cell carcinoma with venous invasion:

Almost 40% of patients with venous invasion are not suffering from metastases (pN0 and M0) and may be cured by surgery. Patients with pN0 M0 have a 5 years survival rate of 70%. 26% have lymph node metastases. 54% have distant metastases.

Prognosis of renal cell carcinoma with systemic metastasis:

Metastatic renal cell cancer is a very aggressive disease. Patients who have metastases at initial diagnosis have a poor prognosis and usually die within the first year. The interval from the nephrectomy to the onset of metastases is important for prognosis, as it provides information on the rate of progression of the systemic disease. Patients with pulmonary metastases have the best prognosis. In addition to metastases in other locations, the following factors indicate a poor prognosis: low Karnofsky index, tumor anemia, abnormal high corrected serum calcium, elevated LDH, elevated AP and missing cytoreductive nephrectomy. The mean survival time is 4–15 months depending on the number of risk factors, see also tab. Motzer criteria for the prognosis of metastatic renal cell carcinoma.

Probability of disease progression after nephrectomy:

The probability of disease progression after nephrectomy can be estimated using the Mayo Scoring System (Leibovich et al., 2003). Risk factors include tumor stage, tumor size, lymph node status, grading and tumor necrosis [see Table Mayo Scoring System].

Mayo Scoring System [Leibovich 2003] to assess the risk of metastases after nephrectomy.
Low-risk cancers (0–2 points) develop in 2% metastases after 3 years and in 7.5% metastases after 10 years.
Intermediate-risk carcinomas (3–5 points) develop in 20% metastases after 3 years and in 36% metastases after 10 years.
High-risk carcinomas (>6 points) develop in 63% metastases after 3 years and in 76% metastases after 10 years.
Risk factor Points
T stage
T1a 0
T1b 2
T2 3
T3–4 4
Tumor size
<10 cm 0
>10 cm 1
Lymph node status
pNx/pN0 0
pN1–2 1
Grading
1–2 0
3 1
4 3
Tumor necrosis
absent 0
present 1
Prognosis of renal cell carcinoma with brain metastases:

Median survival of 7 months.

Prognosis of renal cell carcinoma in relation to age:

A young age at the onset of the disease is associated with a better prognosis, although adverse histological differentiations are more common.

Prognosis depending on the surgical treatment:

Retrospective comparisons between nephrectomy and partial nephrectomy for T1 tumors showed a better survival for patients after partial nephrectomy. This is explained with a reduction of cardiovascular diseases due to the better glomerular filtration rate (Zini, 2009) (Weight, 2010).

Prediction of prognosis with the help of nomograms:

For details see: (Frank et al, 2003), (Kattan et al, 2001), (Zisman et al, 2002).







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