Management of Poor-Risk Metastatic Renal Cell Carcinoma: Current Approaches, the Role of Temsirolimus and Future Directions

Figures & data

Figure 1. Signal transduction pathway involving mTOR.

Figure 2. Kaplan–Meier curves of (A) overall survival and (B) progression-free survival in the Phase III, randomized, multicenter trial of temsirolimus with or without IFN-α in patients with metastatic renal cell carcinoma.

OS: Overall survival; PFS: Progression-free survival.

Reproduced with permission from [11] © 2007 Massachusetts Medical Society.

Table 1. Prognostic criteria to predict survival in patients with advanced renal cell carcinoma: Memorial Sloan–Kettering Cancer Center and Heng criteria.

Risk factors	Threshold value
Risk status (number of risk factors):
– Low	0
– Intermediate	1–2
– High	≥3
MSKCC^†
KPS	<80%
Time from diagnosis to start of systemic treatment	<12 months
Hemoglobin	<Lower limit of laboratory’s reference range
Lactate dehydrogenase	>1.5 × the upper limit of laboratory’s reference range
Corrected serum calcium	>10.0 mg/dl (2.4 mmol/l)
Heng criteria
KPS	<80%
Time from diagnosis to start of systemic treatment	<12 months
Hemoglobin	<Lower limit of laboratory’s reference range
Corrected serum calcium	>10.0 mg/dl (2.4 mmol/l)
Neutrophils	>Upper limit of laboratory’s reference range
Platelets	>Upper limit of laboratory’s reference range

^†Modified in temsirolimus Phase III ARCC trial [11] to include a KPS of 60 or 70, and with the addition of metastases in multiple organs; different MSKCC criteria (low hemoglobin, high corrected calcium, and low performance status [6]) used to assess prognostic risk for second-line everolimus (RECORD-1) [12] and axitinib (AXIS) [13] trials.

KPS: Karnofsky performance status; MSKCC: Memorial Sloan–Kettering Cancer Center; RCC: Renal cell carcinoma.

Data taken from [3–6].

Table 2. Treatment recommendations for patients with metastatic renal cell carcinoma^† based on European and US guidelines.

Treatment status	EAU		ESMO		EORTC-GU expert opinion				NCCN
	Level 1 evidence (grade)	Level 2 evidence (grade)	Level 1 evidence (grade)	Level 2 evidence (grade)	Level 1A evidence	Level 1B evidence	Level 2A evidence	Level 2B evidence	Category 1	Category 2A	Category 2B	Category 3
First-line
Good or intermediate risk	Sunitinib (B) Bevacizumab + IFN-α (B) Pazopanib (B)	–	Sunitinib (A) Bevacizumab + IFN-α (A) Pazopanib (A)	Sorafenib (B; nonstandard option)	Bevacizumab + IFN-α	Sunitinib	–	Sorafenib High-dose IL-2	Sunitinib Bevacizumab + IFN-α Pazopanib	Sorafenib (selected patients) High-dose IL-2 (selected patients) Axitinib	–	–
Poor risk	Temsirolimus (B)	–	–	Temsirolimus (A) Sunitinib (B; nonstandard option)	–	Temsirolimus	–	Sunitinib (alternative)	Temsirolimus^‡	–	–	–
Second-line
Prior cytokine	Sorafenib (B)	Axitinib (A) Pazopanib (A)	Sorafenib (A) Axitinib (A)	Pazopanib (A)	–	Sorafenib	–	–	Axitinib Sorafenib Sunitinib Pazopanib	Temsirolimus Bevacizumab	High-dose IL-2 (selected patients)	–
Prior TKI	–	Nivolumab (A) Cabozantinib (A) Axitinib (A) Everolimus (A)	Axitinib (B)	Everolimus (A) Sorafenib (A; nonstandard option)	–	Everolimus	–	–	Everolimus Axitinib	Sorafenib Sunitinib Pazopanib	Temsirolimus Bevacizumab	–
Prior mTOR inhibitor	No data^§		No data^§		No data^§				No data^§

^†Clear-cell histology.

^‡Category 1 for poor-prognosis patients; category 2B for selected patients of other risk groups.

^§Patients should be encouraged to participate in a clinical trial.

EAU: European Association of Urology; EORTC-GU: European Organisation for Research and Treatment of Cancer Genito-Urinary Group; ESMO: European Society of Medical Oncology; NCCN: National Comprehensive Cancer Network; TKI: Tyrosine kinase inhibitor.

Data taken from [7–9,21–22].

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