Dr. med. Dirk Manski



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Treatment of Metastatic Renal Cell Carcinoma

Prognosis of Metastatic Renal Cell Carcinoma

Motzer from MSKCC developed accepted criteria for the prognosis of metastatic renal cell carcinoma, which are used for the stratification of pations within trials of immunotherapy (Motzer et al, 2002), see table Motzer criteria. The IMDC score is an update with patient data from modern studies with kinase inhibitors and checkpoint inhibitors (Heng et al, 2013), see table IMDC score for survival time of the 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.
Intermediate 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


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IMDC-Score for prognosis of metastatic renal cell carcinoma under therapy with kinase inhibitors and checkpoint inhibitors (Heng et al, 2013):
Low risk (0 risk factors): median overall survival of 43 months.
Intermediate risk (1-2 risk factors): median overall survival of 23 months.
High risk (3 or more risk factors): median overall survival of 8 months
Adverse risk factor Limit
Reduced Karnofsky Index <80%
Elevated neutrophils > upper limit of normal
Elevated platelets > 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

Surgical Therapy of Primary Tumor And Metastases

If a complete resection of all metastases and the primary tumor is possible, surgical therapy should be carried out without neoadjuvant therapy. Depending on the location of the metastases (lungs, liver, bones), appropriate surgical specialists should be consulted. Despite the complete resection of all visible lesions, there is a high risk of recurrence, but surgical therapy can delay the need for drug therapy and probably also improves the patient's prognosis. Another advantage of surgical treatment of metastases is the palliation of local complaints.

The prognosis after removal of a solitary metastasis is less favorable in patients for whom the metastasis already existed at the initial diagnosis. If the metastasis is discovered during the follow-up, the time from initial diagnosis to metastasis is crucial for the prognosis.

Cytoreductive nephrectomy in patients with metastatic renal cell carcinoma:

Cytoreductive nephrectomy is the resection of the primary tumor before drug therapy of metastases, which cannot be removed. In addition to palliation of local complaints, nephrectomy before planned immunotherapy leads to an prolongatio of survival (Mickisch u.a., 2001a). Laparoscopic cytoreductive nephrectomy offers advantages in the metastatic stage due to the shorter convalescence time, the time to start immunotherapy can be reduced.

Two randomized studies (CARMENA and SURTIME) were carried out for cytoreductive nephrectomy prior to therapy with signal transduction inhibitors. Neither study demonstrated any benefits for cytoreductive nephrectomy before sunitinib (Mejean et al, 2018) (Bex et al, 2019), but only patients with medium or high risk were included.

In the current EAU guideline, cytoreductive nephrectomy is only recommended for patients with a small metastasis volume and a large primary tumor. If systemic therapy responds well, delayed cytoreductive nephrectomy can be considered. There is no indication for cytoreductive nephrectomy in patients with high risk, small primary tumor and high metastatic burden, with poor performance status, with Bellini duct carcinoma or sarcomatoid tumors (if the histology is known before surgery).

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.

Checkpoint inhibitors


Recommended sequential therapy for metastatic renal cell carcinoma with inhibitors of immune checkpoints and signal transduction (TKI and mTOR), based on German S3 guidelines. A switch to the next option is necessary only if there is a clear progress or intolerable side effects (despite adjuvant therapy and dose reduction). Solid arrows: first choice. Dotted arrows: alternatives for contraindications.
(1) Refer to table >IMDC criteria to assess prognosis.
flow chart for sequential therapy of metastatic renal cell cancer with inhibitors of immune checkpoints and signal transduction

The activation of immune checkpoint receptors leads to the inhibition and weakening of the cellular immune response. They have a physiological function in preventing autoimmune diseases. Various 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 such as PD-L1. Tumors secrete ligands to immune checkpoints to induce immune tolerance. See section pharmacology and side effects of checkpoint inhibitors (CPI).

The superiority of the combined therapy (tyrosine kinase inhibitor with immune checkpoint inhibitor) over the monotherapy with tyrosine kinase inhibitor (see below) was demonstrated in several studies. In a few cases, the treatment leads to a complete remission. A realistic treatment effect is to achieve a stable disease, in some cases the therapeutic effect is seen delayed after a minor progression of disease. A switch to the next option is necessary only if there is a clear progress or intolerable side effects (despite adjuvant therapy and dose reduction), see fig. sequential therapy of metastatic renal cell carcinoma.

Avelumab combined with axitinib:

The combination improved (compared to sunitinib) progression-free survival (14 vs. 7 months) and response rate (CR 4% vs. 2% and partial response 49% vs. 25%), data for survival have not yet been published (Motzer et al, 2019), the benefit was independent of the IMDC risk classification.

Nivolumab monotherapy:

Improved progression-free survival, response rate (CR + PR: 25% vs. 5%) and overall survival (25 vs. 20 months) as a second-line therapy after TKI failure (compared to everolimus) and showed fewer side effects (Motzer et al, 2015).

Nivolumab combined with ipilimumab:

Showed significant advantages in progression-free survival (11.6 vs. 8.4 months, HR 0.82) and in overall survival (not reached vs 26 months, HR 0.64) in the CheckMate-214 study compared to sunitinib in first-line therapy. The EAU guidelines changed the recommendations for first-line therapy for patients with medium and poor prognosis in favor of nivolumab and ipilimumab (Powles et al, 2017a).

Pembrolizumab combined with axitinib:

Improved progression-free survival, response rate (CR 6% vs. 2%, PR 53% vs. 34%) and overall survival (HR 0.59, 1 year survival rate 90% vs. 79%) (Rini et al, 2019), this was independent of the IMDC risk classification or the PD-L1 expression.

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.

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). Axitinib has gained new importance in first-line therapy as a combination treatment with pembrolizumab or avelumab, see above. Dosage, pharmacology and side effects see 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.

Cabozantinib:

Cabozantinib is an oral inhibitor of tyrosine kinases such as MET, VEGF and AXL. Cabozantinib is approved for the second and third line therapy of metastatic renal cell carcinoma. Compared to everolimus, progression-free survival (7.4 vs. 3.8 months) and overall survival (21 vs. 19 months) were prolonged (Choueiri u.a., 2015). Cabozantinib also showed a higher progression-free survival rate (9 vs. 5 months) in medium and high-risk patients in first-line therapy compared to sunitinib (Choueiri u.a., 2018), so that approval for first-line therapy in medium and low-risk patients was also granted. Dosage, pharmacology and side effects see section cabozantinib.

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), there was a slight improvement (5 vs. 2 months) in progression-free survival compared to placebo. A direct comparison with sunitinib showed a significantly reduced response rate (8% vs. 27%), everolimus is of no importance for the first-line therapy (Knox et al, 2017). Dosage, pharmacology and side effects see 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). Progression-free survival improved significantly (9.2 vs. 4.2 months), the difference was even more pronounced in the subgroup without prior therapy (11.1 vs. 2.8 months). No significant differences could be demonstrated for overall survival. Dosage, pharmacology and side effects see 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 approved for first-line treatment and second-line therapy after interferon therapy of metastasized renal cell carcinoma. Dosage, pharmacology and side effects see 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 With Interferon or Interleukin::

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:

Corticosteroids, irradiation (e.g. Gamma knife).

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:

See table Robson stage and survival for prognosis and clinical stage. More precise results for the survival probability are possible by considering several risk factors, see stage, size, grade, and necrosis (SSIGN) Score [(Assessing SSIGN Score and Survival and SSIGN Score)]. .

Grading and survival:

Five-year survival rates depending of grading: G1 (89%), G2 (65%), G3 (46%).

Prognosis of renal cell carcinoma with lymph node metastasis:

Five-year 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, elevated platelets, elevated neutrophils. See tab. IMDC Score for mean survival time under treatment with TKI and CPI.

Prognosis of renal cell carcinoma with brain metastases:

Median survival of 7 months, prognostic factors are Karnofsky index and number of metastases.







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