Overall survival improvement in patients with metastatic clear-cell renal cell carcinoma between 2000 and 2020: a retrospective cohort study

Figures & data

Table 1. Patient characteristics.

	All	Start 1L 2000-2005	Start 1L 2006-2011	Start 1L 2012-2017	Start 1L 2018-2020	Start with IFNa	Start with VEGFR-TKI	Start with ICI
Patient characteristics at diagnosis
Number of patients	500	88	146	180	86	92	330	57
Age, median (years)	65	64	66	65	66	64	65	64
Male	65.0%	61.4%	58.9%	70.6%	67.4%	60.9%	65.8%	70.2%
	325/500	54/88	86/146	127/180	58/86	56/92	217/330	40/57
Tumor characteristics at diagnosis
Fuhrman grades 1–2	17.4%	20.3%	16.8%	18.5%	13.3%	19.4%	17.0%	21.3%
	78/449	14/69	23/137	31/168	10/75	14/72	53/312	10/47
Nephrectomy at diagnosis
Nephrectomy	87.0%	86.4%	88.4%	89.4%	80.2%	87.0%	89.4%	75.4%
	435/500	76/88	129/146	161/180	69/86	80/92	295/330	43/57
Patient characteristics at start of systemic therapy
Time between diagnosis and start systemic therapy < 12 months	53.0%	54.5%	53.4%	52.2%	52.3%	54.3%	52.4%	50.9%
	265/500	48/88	78/146	94/180	45/86	50/92	173/330	29/57
Site of metastasis
Bone	39.6 %	42.0%	42.5%	41.7%	27.9%	40.2%	39.7%	36.8%
	198/500	37/88	62/146	75/180	24/86	37/92	131/330	21/57
Liver	22.0%	21.6%	22.6%	21.7%	22.1%	21.7%	23.6%	14.0%
	110/500	19/88	33/146	39/180	19/86	20/92	78/330	8/57
Lung	68.8%	77.3%	71.9%	66.1%	60.5%	78.3%	65.2%	64.9%
	344/500	68/88	105/146	119/180	52/86	72/92	215/330	37/57
Brain	7.2%	10.2%	8.2%	6.1%	4.7%	10.9%	6.1%	3.5%
	36/500	9/88	12/146	11/180	4/86	10/92	20/330	2/57
Median number of metastatic sites (n, range)	3 (0–9)	3 (0–9)	3 (1–8)	2 (1–6)	2 (1–7)	3 (0–9)	2 (1–8)	2 (1–6)
Karnofsky performance status < 80	33.0%	39.5%	35.8%	27.6%	32.5%	40%	28.9%	29.8%
	156/473	34/86	48/134	47/170	27/83	36/90	88/305	17/57
Serum albumin ≤ 3.5 g/dl	14.25%	25%	7.0%	17.0 %	10.5%	24.3%	12.4%	5.6%
	57/400	17/68	8/115	24/141	8/76	17/70	32/258	3/54
Neutrophils ≥ 7800/mm³	14.0%	16.1%	10.1%	19.3%	4.9%	17.6%	14.1%	7.1%
	67/479	14/87	14/139	33/171	4/82	16/91	44/311	4/56
Platelets ≥ 450,000/mm³	13.5%	13.6%	11.5%	15.7%	12.0%	13.0%	14.4%	8.8%
	65/482	12/88	16/139	27/172	10/83	12/92	45/312	5/57
CRP > 5 mg/L	67.3	72.1%	72.5%	64.5%	58.0%	72.2%	65.7%	57.9%
	318/474	62/86	100/138	109/169	47/81	65/90	201/306	33/57
Corrected serum calcium > 10.2 mg/dl	7.1%	11.8%	7.8%	6.5%	4%	10%	6.3%	3.8%
	28/397	8/68	9/115	9/139	3/75	7/70	16/256	2/53
Low hemoglobin (< 14 g/dl for men, < 12 g/dl for women)	59.6%	63.6%	57.1%	59.2%	61.4%	63.0%	57.8%	61.4%
	289/485	56/88	80/140	103/174	51/83	58/92	182/315	35/57
IMDC score
Good	17.0%	16.5%	11.9%	21.2%	17.3%	16.9%	17.4%	19.6%
	80/470	14/85	16/134	36/170	14/81	15/89	53/304	11/56
Intermediate	53.6%	44.7%	59.7%	48.8%	63.0%	44.9%	55.6%	57.1%
	252/470	38/85	80/134	83/170	51/81	40/89	169/304	32/56
Poor	29.4%	38.8%	28.4%	30%	19.8%	38.2%	27.0%	23.2%
	138/470	33/85	38/134	51/170	16/81	34/89	82/304	13/56

Note: 1 L: first-line; IFNa: interferon-alpha; VEGFR-TKI: vascular endothelial growth factor receptor tyrosine kinase inhibitor; ICI: immune checkpoint inhibitor; CRP: C-reactive protein; IMDC: International Metastatic RCC Database Consortium.

Figure 1. Kaplan–Meier estimates of median overall survival (OS) correlated to start year (panel A) and correlated to first-line therapy (panel B). ICIs: immune checkpoint inhibitors; VEGFR-TKI: vascular endothelial growth factor receptor tyrosine kinase inhibitor; IFN: interferon-alpha.

Figure 2. One to five-year survival probabilities depending on start year and availability of treatments (in Belgium). The combination of axitinib/pembrolizumab and axitinib/avelumab became available in 2020.

Table 2. One, two, three, four and five-year overall survival depending on starting year and first-line treatment.

	1Y OS	2Y OS	3Y OS	4Y OS	5Y OS
Depending on start year
2000–2005	49%	23%	15%	14%	7%
2006–2011	58%	34%	22%	18%	14%
2012–2017	69%	50%	40%	28%	24%
2018–2020	73%	59%	/	/	/
Depending on first-line treatment
IFNa	51%	22%	14%	12%	7%
TKI	64%	43%	33%	25%	21%
ICI	75%	71%	62%	44%	36%

Y: year; OS: overall survival; IFNa: interferon-alpha; VEGFR-TKI: vascular endothelial growth factor receptor tyrosine kinase inhibitor; ICI: immune checkpoint inhibitor.

Table 3. Univariable and multivariable analysis.

Variable	Test	Hazard ratio (95% CI)	p-value
Univariable analysis
Year (linear)	+1 year	0.947 (0.930;0.965)	<0.0001
Year (non-linear)	Quadratic effect		0.0092
	2001 v 2000	1.029 (0.964;1.097)	0.3942
	2006 v 2005	0.982 (0.950;1.015)	0.2789
	2011 v 2010	0.937 (0.918;0.957)	<0.0001
	2016 v 2015	0.895 (0.853;0.938)	<0.0001
Multivariable analysis (non-linear)
IMDC	Global test		<0.0001
	Good v intermediate	0.585 (0.407;0.841)	0.0038
	Good v poor	0.340 (0.231;0.501)	<0.0001
	Intermediate v poor	0.581 (0.459;0.736)	<0.0001
CRP	>5mg/l v ≤5mg/l	2.213 (1.691;2.897)	<0.0001
Bone metastases	Present v Absent	1.072 (0.864;1.331)	0.5276
Brain metastases	Present v Absent	2.441 (1.668;3.573)	<0.0001
Year (non-linear)	Quadratic effect		0.0104
	2001 v 2000	1.039 (0.965;1.118)	0.3141
	2006 v 2005	0.987 (0.950;1.025)	0.5031
	2011 v 2010	0.938 (0.917;0.959)	<0.0001
	2016 v 2015	0.892 (0.848;0.938)	<0.0001

Note: HR<(>)1 means lower (higher) risk for a later start of therapy. In the non-linear model (both univariable and multivariable), the indicated HR do not compare two single treatment years but give an indication of the global slope of the curve at different time points. CI: confidence interval, CRP: C-reactive protein; IMDC: International Metastatic RCC Database Consortium; v: versus.

Figure 3. Panels A and B: Number of lines of therapy received by the patients depending on starting year. Panel A: scatter plot with smoothed curve and spearman correlation. Panel B: mean number of lines of therapy over time with 95% confidence interval.