Impact of aristolochic acid exposure on oncologic outcomes of upper tract urothelial carcinoma after radical nephroureterectomy

Figures & data

Table 1 AA exposure by clinical and pathological characteristics in 942 patients treated with RNU for UTUC

Variable	None/possible AA (n=856), (%)	AA n=86, (%)	AA exposure duration		p-value
			≤6 years AA n=57, (%)	>6 years AA n=29, (%)	None/possible vs all AA	None/possible vs ≤6 year AA	None/possible vs >6 year AA	≤6 year AA vs >6 year AA
Age (years)
<65	280 (32.7)	37 (43.0)	24 (42.1)	13 (44.8)	0.06	0.15	0.17	0.81
≥65	576 (67.3)	49 (57)	33 (57.9)	16 (55.2)
Gender
Male	399 (46.6)	25 (29.1)	20 (35.1)	5 (17.2)	0.002	0.09	0.002	0.09
Female	457 (53.4)	61 (70.9)	37 (64.9)	24 (82.8)
Tobacco consumption
Yes	146 (17.1)	7 (8.1)	6 (10.5)	1 (3.4)	0.03	0.20	0.05	0.26
No	710 (82.9)	79 (91.9)	51 (89.5)	28 (96.6)
Tumor side
Left	440 (51.4)	42 (48.8)	31 (54.4)	11 (37.9)	0.65	0.66	0.15	0.15
Right	416 (48.6)	44 (51.2)	26 (45.6)	18 (62.1)
Main tumor location
Pelvis	447 (52.2)	61 (70.9)	43 (75.4)	18 (62.1)	0.001	0.001	0.30	0.20
Ureter	409 (47.8)	25 (29.1)	14 (24.6)	11 (37.9)
Main tumor size (cm)
≤3	415 (48.5)	43 (50.0)	23 (40.4)	20 (69.0)	0.79	0.23	0.03	0.01
>3	441 (51.5)	43 (50.0)	34 (59.6)	9 (31.0)
Multifocality
Presence	617 (72.1)	63 (73.3)	44 (77.2)	19 (65.5)	0.82	0.40	0.44	0.25
Absence	239 (27.9)	23 (26.7)	13 (22.8)	10 (34.5)
Preoperative eGFR, mL/min
>30	84 (9.8)	25 (29.1)	14 (24.6)	11 (37.9)	<0.001	<0.001	<0.001	0.20
≤30	722 (84.3)	61 (70.9)	43 (75.4)	18 (62.1)
Concomitant CIS
Presence	18 (2.1)	4 (4.7)	2 (3.5)	2 (6.9)	0.14	0.48	0.08	0.48
Absence	838 (97.9)	82 (95.3)	55 (96.5)	27 (93.1)
Tumor stage
≤T2	598 (69.9)	69 (80.2)	46 (80.7)	23 (79.3)	0.04	0.08	0.27	0.88
≥T3	258 (30.1)	17 (19.8)	11 (19.3)	6 (20.7)
Tumor grade
G1–G2	514 (60.0)	52 (60.5)	35 (61.4)	17 (58.6)	0.94	0.84	0.05	0.80
G3	342 (40.0)	34 (39.5)	22 (38.6)	12 (41.4)
Lymph node status
cN0 or pN0	758 (88.6)	84 (97.7)	55 (96.5)	29 (100.0)	0.009	0.06	0.05	0.30
pN +	98 (11.4)	2 (2.3)	2 (3.5)	0 (0.0)

Note: The number in bold indicates statistically significant. p<0.05.

Abbreviations: AA, aristolochic acids; RNU, radical nephroureterectomy; UTUC, upper tract urothelial carcinoma; CIS, carcinoma in situ; eGFR, estimated glomerular filtration rate.

Figure 1 Estimated Kaplan–Meier cancer-specific survival curves (A), intravesical recurrence-free survival curves (B) and contralateral UTUC recurrence-free survival curves (C) stratified by AA exposure history.

Abbreviations: AA, aristolochic acids; UTUC, upper tract urothelial carcinoma.

Table 2 Multivariate Cox regression analysis predicting time to intravesical recurrence and cancer-specific mortality in 942 patients treated with RNU for UTUC

Variable	Intravesical recurrence			Cancer-specific mortality
	HR	95% CI	p-value	HR	95% CI	p-value
Gender (male vs female)	1.28	0.987–1.693	0.07	1.503	1.137–2.044	0.006
Age (≤65 vs >65 years)	1.09	0.749–1.268	0.84	1.260	0.934–1.701	0.13
Tobacco consumption (presence vs absence)	0.80	0.548–1.171	0.25	1.205	0.838–1.732	0.31
AA exposure history (presence vs none/possible)	2.117	1.488–3.013	<0.001	0.436	0.214–0.888	0.022
Tumor side (left vs right)	0.83	0.647–1.066	0.14	0.995	0.758–1.307	0.97
Main tumor location (ureter vs pelvis)	1.34	1.039–1.752	0.025	1.036	0.771–1.391	0.82
Main tumor size (≤3 vs >3 cm)	0.68	0.521–0.882	0.004	1.231	0.914–1.658	0.17
Multifocality (presence vs absence)	1.15	0.874–1.524	0.31	0.730	0.530–1.007	0.06
Concomitant CIS (presence vs absence)	1.35	0.683–2.682	0.39	0.97	0.425–2.203	0.94
Tumor stage (Ta/Tis/T1–2 vs T3–4)	0.97	0.696–1.340	0.83	2.160	1.573–2.967	<0.001
Tumor grade (G1–2 vs G3)	0.75	0.563–0.998	0.049	1.594	1.165–2.181	0.004
Lymph node status (cN0/pN0 vs pN +)	0.36	0.191–0.666	0.001	1.358	0.918–2.010	0.13
AA exposure duration*			<0.001			0.07
≤6 year vs possible/none	1.699	1.075–2.685	0.023	0.534	0.250–1.140	0.11
>6 year vs possible/none	2.990	1.817–4.922	<0.001	0.190	0.026–1.363	0.10

Note:

* All models were adjusted for the effects of age (≤65 vs >65 years), gender, tobacco consumption, tumor size, tumor location (ureter vs pelvis), main tumor size (≤3 vs >3 cm), multifocality, lymph node metastasis (cN0/pN0 vs pN +), pathologic grade (G1–2 vs G3), pathologic stage (Ta/Tis/T1–2 vs T3–4) and concomitant carcinoma in situ. The number in bold indicates statistically significant. p<0.05.

Abbreviations: AA, aristolochic acids; HR, hazard ratio; RNU, radical nephroureterectomy; UTUC, upper tract urothelial carcinoma.

Figure 2 Estimated Kaplan–Meier cancer-specific survival curves (A), intravesical recurrence-free survival curves (B) stratified by the exposure duration, and estimated Kaplan–Meier cancer-specific survival curves (C), intravesical recurrence-free survival curves (D) stratified by time since last AA exposure.

Abbreviation: AA, aristolochic acids.