Efficacy of Cytoreductive Surgery for Metastatic Upper Tract Urothelial Carcinoma: A Surveillance, Epidemiology and End Results (SEER) study of 508 patients

doi:10.21203/rs.3.rs-3131854/v1

Objective

To explore the role of cytoreductive surgery (CRS) in patients with metastatic upper tract urothelial carcinoma (mUTUC) receiving different types of adjuvant therapy.

Material and Methods

Data from 9,436 anonimized records was abstracted from the Surveillance, Epidemiology, and End Results (SEER) database between 2008–2018. Of these, 508 individuals had received adjuvant therapy subsequent to being diagnosed with mUTUC. These patients had all been treated with adjuvant therapies such as chemotherapy and/or radiotherapy. Patients were stratified into either a non-surgical or surgical group based on CRS status before adjuvant therapeutics commenced. Kaplan-Meier curves were used to compare OS and CSS. Cox’s proportional hazard models were then used to analyze prognostic factors related to OS and CSS.

Results

Of the 508 cases, 36.8% (n = 187) had received CRS with adjuvant treatments. The remaining 63.2% (n = 321) received either chemotherapy and/or radiotherapy alone. Kaplan-Meier curves showed that 11.6% had 3-yr OS (95%CI 7.1–17.3) for CRS with adjuvant treatment and 4.9% (95%CI 2.7–8.0) for adjuvant treatment alone (p = 0.001). The 3-yr CSS was 14.9% for CRS plus adjuvant treatment (95%CI 9.4–21.7) and 6.0% (95%CI 3.4–9.8) for adjuvant treatments alone (p = 0.003). Under multivariate regression analysis, primary ureter site OS had a hazard ratio (HR) of 0.74 (95%CI 0.58–0.95, p = 0.019) and a CSS HR of 0.72 (95%CI 0.56–0.94, p = 0.014). The CRS OS HR was 0.79 (95%CI 0.65–0.95, p = 0.015) and the CSS HR was 0.75 (95%CI 0.61–0.92, p = 0.006). Additionally, chemotherapy had an OS HR of 0.46 (95%CI 0.33–0.0.65, p < 0.001) and a CSS HR of (0.44, 95%CI 0.31–0.63, p < 0.001). Bones and liver metastases were also indicative of poorer prognosis. Validation was conducted through subgroup analysis which suggested CRS was effective only for patients who received chemotherapy or combined chemo-radiotherapy but not for radiotherapy alone.

Conclusions

CRS provided significantly increased OS and CCS for mUTUC patients who received chemotherapy or combined chemo-radiotherapy in this study. In addition, the primary tumor and metastatic sites were related to improved patient survival although this was a small, relatively homogeneous sample therefore further research is required.

cytoreductive surgery

adjuvant treatment

metastatic upper tract urothelial carcinoma

overall survival

cancer-specific survival

Approximately 10% of all patients with upper tract urothelial carcinoma (UTUC) present with extraregional lymph nodes and/or other distant site metastases (1). This can vary substantially according to both demographics and clinical characteristics (2). Unfortunately, prognosis for these individuals is poor, with 3-yr overall survival (OS) rates for metastatic upper tract urothelial carcinoma (mUTUC) not exceeding 10% (1). Besides, there are also differences in relation to treatment combinations. For example, Thomas et al.'s study based on National Cancer Database showed that the 3-yr OS of chemotherapy combined with radical nephroureterectomy was better than chemotherapy alone, with rates of 16.2% and 6.4%, respectively (3). Conversely, Necchi et al.'s study suggested that adjuvant chemotherapy after radical nephrectomy did not increase survival in patients with UTUC (4).

It remains unclear whether radiotherapy alone or in combination with other treatment modalities has a positive impact on prognosis for patients with UTUC (5). We do not yet know enough about treatment combinations and we do not yet know which patients will respond best to which combination and dosing, timing etc. Cisplatin-based combination chemotherapy alone is currently considered the standard of care for otherwise healthy patients with mUTUC (6). However, the metastatic tumor treatment paradigm is evolving and increasingly evidence suggests there are benefits to controlling the primary focus, specifically for metastatic urothelial carcinoma (7). However, these are relatively rare tumors and so there are very few randomized controlled trials which compare treatment modalities. Indeed, there is very little evidence available or even data related to cytoreductive surgery (CRS) for mUTUC. A recent study by Xia et al. suggested CRS outcomes improve when supplemented with chemotherapy although this was only preliminary research which requires further investigation (8).

The Surveillance, Epidemiology, and End Results (SEER) database is a publicly available national data source developed in the US. Data for the SEER database are collected through local registries in 18 + US states. The purpose of the SEER database is to record time trends, pathologic evidence and treatment data as well as demographics and socio-economics etc. This data source makes it possible to analyse anonymized patient data to identify trends in primary data, which is especially useful for low prevalence diseases such as mUTUC. The objective of this study was to explore SEER data to understand the impact of CRS on OS and cancer-specific survival (CSS) for mUTUC patients who received adjuvant treatment/s.

Population

We extracted pertinent data from the SEER database in November 2020. The sample identified was of those diagnosed and treated between 2008–2018. Inclusion criteria were as follows: (1) primary tumor was identified using the International Classification of Diseases-O-3 (ICD-O-3) codes C64.9, C65.9; (2) initial primary tumor was confirmed to be renal pelvis or ureter carcinoma, and (3) histology was microscopically confirmed. Patients were excluded if metastasis, survival months, and vital status were unknown, and when the tumor was considered a secondary lesion.

Description of covariates

Factor analysis included age, sex, ethnic origin, primary tumor sites, clinical T stage (AJCC, 7th edition, 2010), clinical N stage (AJCC, 7th edition, 2010), radiotherapy, chemotherapy, surgery and metastatic sites (bone, liver, brain and lung).

Statistical Analysis

Kaplan-Meier survival curves were calculated and compared using the Log-rank test. Univariate analyses were used to assess associations between potential prognostic factors i.e. age, gender, ethnic origin, primary site, tumor stage, CRS, adjuvant treatment regimen, metastatic site and survival. A standard Chi-squared test was used for categorical variables and an unpaired Student’s t test was used to analyze outcomes in relation to age. Significant variables under univariate analyses were entered into a multivariate analysis (Cox stepwise-regression). P values of less than 0.05 were considered significant. All tests were conducted with SPSS (version 26.0).

Patient’s Characteristics

Data for 9,436 anonimized patients were enrolled from the SEER database, of whom 508 individuals received adjuvant therapy subsequent to being diagnosed with mUTUC. The median age of this sample was 67 years. 38.8% (n = 197) were women and 84.3% (n = 428) were caucasian. All patients had received adjuvant treatment (either chemotherapy and/or radiotherapy) based on condition specifics.

Table 1 compares patient characteristics and clinical features of those who received CRS (n = 187) and the population who did not receive CRS (n = 321). Compared to patients who did not receive CRS, patients with CRS had higher clinical T stages (p < 0.001). There were no significant differences in relation to age, sex, ethnic origin, primary tumor sites, N stages, chemotherapy, radiotherapy, or metastatic sites between the groups, indicating these two groups were comparable.

Table 1

Baseline characteristics of patients who received adjuvant treatment plus cytoreductive surgery versus adjuvant treatment alone for metastatic upper tract urothelial carcinoma study populations from the SEER data base, 2008–2018
Characters		Overall, n (%)		Cytoreductive surgery, n (%)		Non-cytoreductive surgery, n (%)
n		508		187		321
age		69	(61–72)	69	(62–75)	69	(61–77)	0.966
sex								0.774
	male	311	61.2%	116	62.0%	195	60.7%
	female	197	38.8%	71	38.0%	126	39.3%
race								0.938
	White	428	84.3%	156	83.4%	272	84.7%
	Black	35	6.9%	13	7.0%	22	6.9%
	others	45	8.8%	18	9.6%	27	8.4%
Primary site								0.904
	Renal pelvic	417	82.1%	153	81.8%	264	82.2%
	ureter	91	17.9%	34	18.2%	57	17.8%
T								< 0.001
	T1	111	21.9%	9	4.8%	102	31.8%
	T2	40	7.9%	6	3.2%	34	10.6%
	T3	183	36.0%	95	50.8%	88	27.4%
	T4	174	34.3%	77	41.2%	97	30.2%
N								0.602
	N0	172	33.9%	66	35.3%	106	33.0%
	N1 ~ 3	336	66.1%	121	64.7%	215	67.0%
Chemotherapy								0.24
	No	66	13.0%	20	10.7%	46	14.3%
	Yes	442	87.0%	167	89.3%	275	85.7%
Radiotherapy								0.181
	No	354	69.7%	137	73.3%	217	67.6%
	Yes	154	30.3%	50	26.7%	104	32.4%
Bone metastases								0.25
	No	271	53.3%	106	56.7%	165	51.4%
	Yes	237	46.7%	81	43.3%	156	48.6%
Brain metastases								0.147
	No	489	96.3%	183	97.9%	306	95.3%
	Yes	19	3.7%	4	2.1%	15	4.7%
Liver metastases								0.089
	No	418	62.6%	126	67.4%	192	59.8%
	Yes	190	37.4%	61	32.6%	129	40.2%
Lung metastases								0.667
	No	210	41.3%	75	40.1%	165	42.1%
	Yes	298	58.7%	112	59.9%	186	57.9%
Distant lymph node metastases								0.6
	No	460	90.6%	171	91.4%	289	90.0%
	Yes	48	9.4%	16	8.6%	32	10.0%
Other metastases								0.096
	No	484	95.3%	184	97.3%	302	94.1%
	Yes	24	4.7%	5	2.7%	19	5.9%

Survival analysis based on CRS

The median follow-up was 8.0 months (interquartile range 4.0–14.0). By 2018, approximately 88.4% (n = 449) patients had died. Among these patients, 409 died as a result of developing UUT-UCs and 40 through other causes.

Kaplan-Meier curves (Fig. 1) highlighted a 3-yr OS of 11.6% (95% confidence interval [CI] 7.1–17.3) for CRS plus adjuvant treatment and 4.9% (95%CI 2.7–8.0) for those who received adjuvant treatment alone (p = 0.001). The 3-yr CSS was 14.9% (95%CI 9.4–21.7) for CRS plus adjuvant treatment and 6.0% (95%CI 3.4–9.8) for adjuvant treatment alone (p = 0.003).

Under Cox’s regression analysis (Table 2), CRS was associated with a significant OS (HR 0.79, 95%CI 0.65–0.95; p = 0.015) and CCS (HR 0.75, 95%CI 0.61–0.92; p = 0.006) benefit. Similar results were observed for patients with primary ureter site (OS HR 0.74, 95%CI 0.58–0.95, p = 0.019 and CSS HR 0.72, 95%CI 0.56–0.94, p = 0.014). This was consistent for chemotherapy which had an OS HR of 0.46 (95%CI 0.33–0.65, p < 0.001) and a CCS HR of 0.44 (95%CI 0.31–0.63, p < 0.001). In addition, metastatic bone sites (CCS HR 1.31, 95%CI 1.07–1.62, p = 0.01) and liver (OS HR 1.46, 95%CI 1.21–1.78, p < 0.001; CCS: HR 1.46, 95%CI 1.19–1.79, p < 0.001) had poor survival.

Table 2

Univariate and multivariate cox regression models predicting overall survival and cancer-specific survival of metastatic upper tract urothelial carcinoma after cytoreductive surgery
Characters		Overall survival				Cancer-specific survival
		Univariate analysis		Multivariate analysis		Univariate analysis		Multivariate analysis
		HR (95%CI)	p	HR (95%CI)	p	HR (95%CI)	p	HR (95%CI)	p
Age		1.00 (0.99–1.01)	0.504			1.00 (0.99–1.01)	0.749
Sex
	Male	ref				ref
	Female	1.10 (0.91–1.33)	0.309			1.12 (0.92–1.37)	0.255
Race			0.132				0.077
	White	ref				ref
	Black	1.46 (1.01–2.11)	0.042			1.58 (1.06–2.35)	0.024
	Others	0.74 (0.26–2.13)	0.576			0.65 (0.19–2.21)	0.493
Primary site
	Pelvic	ref				ref
	Ureter	0.76 (0.60-0.976)	0.031	0.74 (0.58–0.95)	0.019	0.75 (0.58–0.97)	0.028	0.72 (0.56–0.94)	0.014	0.014
T			0.097				0.192
	T1	ref				ref
	T2	0.78 (0.60-1.00)	0.053			0.78 (0.59–1.02)	0.068
	T3	0.95 (0.66–1.35)	0.763			0.98 (0.68–1.42)	0.91
	T4	0.78 (0.63–0.97)	0.028			0.82 (0.65–1.03)	0.089
N
	N0	ref				ref
	N1 ~ 3	0.99 (0.81–1.20)	0.919			0.99 (0.81–1.22)	0.957
Cytoreductive surgery
	No	ref				ref
	Yes	0.76 (0.62–0.92)	0.005	0.79 (0.65–0.95)	0.015	0.73 (0.59–0.89)	0.002	0.75 (0.61–0.92)	0.006	0.006
Chemotherapy
	No	ref				ref
	Yes	0.45 (0.34–0.59)	< 0.001	0.46 (0.33–0.65)	< 0.001	0.43 (0.32–0.57)	< 0.001	0.44 (0.31–0.63)	< 0.001	<0.001
Radiotherapy
	No	ref				ref
	Yes	1.32 (1.08–1.62)	0.006	0.94 (0.77–1.32)	0.936	1.35 (1.09–1.67)	0.005	0.99 (0.75–1.31)	0.93	0.93
Bone metastases
	No	ref				ref
	Yes	1.21 (1.01–1.46)	0.043	1.22 (1.00-1.49)	0.054	1.30 (1.07–1.58)	0.008	1.31 (1.07–1.62)	0.01
Brain metastases
	No	ref				ref
	Yes	1.78 (1.11–2.86)	0.018	1.18 (0.71–1.96)	0.523	1.74 (1.05–2.88)	0.031	1.16 (0.68–1.99)	0.59
Liver metastases
	No	ref				ref
	Yes	1.44 (1.19–1.74)	< 0.001	1.46 (1.21–1.78)	< 0.001	1.43 (1.17–1.75)	< 0.001	1.46 (1.19–1.79)	< 0.001
Lung metastases
	No	ref				ref
	Yes	0.95 (0.79–1.14)	0.57			0.92 (0.76–1.12)	0.416
Distant lymph node metastases
	No	ref				ref
	Yes	0.99 (0.69–1.43)	0.976			0.99 (0.68–1.44)	0.955
Other metastases
	No	ref				ref
	Yes	0.81 (0.50–1.29)	0.368			0.84 (0.51–1.36)	0.471

Subgroup analysis based on different adjuvant treatment

Due to significant differences in radiotherapy under both univariate analysis and multivariate analysis, we further explored the role of different adjuvant treatments through subgroup analyses. Among all cases, 69.7% (n = 354) patients received chemotherapy alone as adjuvant treatment, 13.0% (n = 66) received radiotherapy alone as adjuvant treatment, and 17.3% (n = 88) received combined chemoradiotherapy (Table 3).

Table 3

Patients receiving CRS in different adjuvant therapy groups
Adjuvant treatment	Overall, n (%)		Cytoreductive surgery, n (%)		Non-cytoreductive surgery, n (%)
Chemotherapy alone	354	69.7%	137	73.3%	217	67.6%
Radiotherapy alone	66	13.0%	20	10.7%	46	14.3%
Combined chemoradiotherapy	88	17.3%	30	16.0%	58	18.1%

In patients who recieved radiotherapy alone, CRS had no effect on OS (surg. vs non-surg. 6.5 (95%CI 4.2–8.7) months vs 5.8 (95%CI 3.6-8.0) months, p = 0.400) or CCS (surg. vs non-surg. 6.8 (95%CI 4.4–9.1) months vs 6.2 (95%CI 3.8–8.7) months, p = 0.445). Whereas, in patients treated with chemotherapy, OS: surg. vs non-surg. 15.8 months (95%CI 12.8–18.7) vs 12.0 months (95%CI 10.2–12.8), p = 0.046. For CSS: surg. vs non-surg. 18.1 months (95%CI 14.6–21.6) vs 12.9 months (95%CI 10.9–14.9), p = 0.015. Combined chemoradiotherapy had an OS fr surg. vs non-surg. 18.5 months (95%CI 11.4–25.7) vs 10.5 months (95%CI 7.5–13.5), p = 0.032. CSS for surg. vs non-surg were significantly different at 19.2 months (95%CI 11.9–26.4) vs 11.9 months (95%CI 7.8–16.0), p = 0.049. CRS also had a significant benefit on both OS and CCS (Fig. 2).

Upper urinary tract urothelial carcinoma is a relatively rare disease, accounting for 5–10% of all urothelial malignancies (9). However, OS for patients with UTUC is generally lower than for those with bladder cancer. The reason is that most (> 60%) of UTUC patients had early invasion at diagnosis, which only occurred in 15%-25% of bladder urothelial carcinoma (BUC) patients (10). Worse still, approximately 10% of patients with UTUC present with locally advanced cancer or metastasis at initial diagnosis, whose prognosis is poor, with a 3-year OS lower than 10% (11). Therefore, greater consideration must be given to addressing the treatment of metastatic UTUC patients.

This investigation utilized data from the SEER database involved analyzing information collected from 508 patients. Of this group, 36.8% (187/508) underwent CRS while 63.2% (321/508) received adjuvant treatment alone. In the queue, the median survival was only 8.0 months, 88.4% patients (449/508) had succumbed by 2018, which is consistent with the known ominous prognosis of mUTUC (11). Through survival analysis and impact factor analysis, we found that different combinations of CRS and adjuvant therapy had a significant impact on the prognosis of patients. Furthermore, we also obtained evidence of the effect of the primary site and metastatic site of the tumor on the prognosis.

Among patients who received adjuvant therapy, those who also received CRS had better survival, and CRS was associated with survival in multivariate analysis. There is a dearth of literature detailing the usage of CRS for metastatic urologic tumors. Although the CARMENA trial established that systemic therapy was noninferior to cytoreductive nephrectomy, prior to this clinical study, surgery combined with cytokine therapy was commonly accepted as standard therapy for metastatic renal cell carcinoma (12, 13). In bladder cancer literature, local therapy has been demonstrated to provide survival benefits when compared to patients treated with chemotherapy only (14, 15). A National Cancer Database study reported a survival benefit for surgery in 173 patients with cM1 UTUC, regardless of chemotherapy administration (7). Our study, with a larger sample size than previous studies, cautiously supports the integration of consolidative surgery along with perioperative systemic therapy for UTUC that may better define the role of surgery in advanced UTUC.

As has been reported in previous studies, advanced UTUC can be responsive to systemic chemotherapy. For decades, cisplatin-based regimens have been known as most the active first-line agents (16). MVAC became the primary regimen for metastatic UTUC after exhibiting a survival benefit with an improved median survival of 13 months, despite significant toxicity (17). Recently, combination GC therapy has been indicated to be better tolerated than MVAC with similar efficacy. One trial uncovered similar OS (13.8 months with GC vs 14.8 months with MVAC) with patients who received GC experiencing fewer toxic side effects (18). The use of cisplatin-based chemotherapy is widely considered in patients with eGFR > 45 mL/min (16). Furthermore, with the emergence of checkpoint inhibition in primary and maintenance settings, there may exist an opportunity to further characterize the role of CRS for surgically fit patients requiring symptom palliation (such as recalcitrant pain, hematuria, or collecting system obstruction) (16), which holds the promise of enhancing patient quality of life and prolonging survival.

It is crucial to understand that in both OS and CCS analyses, radiotherapy showed a correlation with survival in univariate regression but not in multivariate regression. This may be due to the fact that radiotherapy is a local treatment that can alleviate tumor-related symptoms and tumor growth rate, but it may not directly improve patient prognosis (12). Besides, the use of radiotherapy alone typically occurs in advanced patients who may not be eligible for surgical treatment. As a result, other negative factors caused by advanced tumors may outweigh the benefits of treatment, leading to poorer patient survival (5). However, a recent study conducted by Zhang et al. in 2021 suggested that radiotherapy can be beneficial to OS in UTUC patients, particularly in patients with N1/2/3 (19). Consequently, the efficacy of adjuvant radiotherapy alone and in combination with other treatment modalities necessitates further investigation.

We also examined the impact of CRS on the three groups of patients (chemotherapy alone, radiotherapy alone, and combined chemoradiotherapy) by subdividing the specific adjuvant therapy for each patient. The results revealed that CRS improved the survival outcomes of patients with chemotherapy alone or combined chemoradiotherapy, but did not have any survival benefits for patients with radiotherapy alone. The primary reason that CRS enhanced the prognosis of patients receiving chemotherapy was its ability to reduce the local tumor burden, resulting in a better response to chemotherapy (3, 14). However, for patients with mUTUC, the lack of systemic treatment for the systemic tumor implies that radiotherapy alone or radiotherapy after CRS has no effect on the overall prognosis.

In addition, our cox regression analysis showed that the primary tumor site was associated with patient survival. Previous research has suggested that patients with renal pelvis urothelial carcinoma have better OS compared to patients with ureter urothelial carcinoma (20). This is attributed to the fact that the exogenous ureter is relatively thinner and has a higher possibility of tumor invasion into the peripheral lymphatic and vascular network (20). However, we found that once metastasis occurs, patients with ureter urothelial carcinoma tend to have a better prognosis. In our opinion, if renal pelvis urothelial carcinoma can penetrate the barrier of renal parenchyma and surrounding adipose tissue, it indicates an extremely advanced primary tumor, which is typically associated with a poorer prognosis.

Consistent with previous studies, our research found that lung metastasis was the most common, followed by bone and liver metastases. Brain metastasis is a relatively rare occurrence (21, 22). While several retrospective studies have found that metastasis to specific organs such as the liver and bone may predict a poorer prognosis, most researchers agree that the number of metastatic organs, which reflects the overall tumor burden, is a stronger predictor of prognosis in mUTUC than the presence of visceral metastasis alone (22). Therefore, it is important to consider the extent of metastasis, along with other prognostic factors, when determining the optimal treatment approach for patients with mUTUC.

Our investigation had several limitations. Firstly, we lacked information regarding the treatment sequence, which limited our ability to fully assess the impact of these variables on patient outcomes. Secondly, we were unable to determine the specific types and number of cycles administered for systemic chemotherapy, as well as those who received radiotherapy in conjunction with or after chemotherapy, due to a lack of granularity in the SEER summary variable. Furthermore, since the SEER database did not provide further description of functional characteristics, we were unable to analyze the impact of complications and functional status on patient outcomes. These limitations highlight the need for more detailed and comprehensive data collection in future studies to better understand the factors that influence prognosis in patients with mUTUC.

In conclusion, our study found that fit patients with mUTUC who received CRS had improved OS and CSS. Although the observational study design introduces certain biases and limitations, our preliminary findings provide strong evidence for the potential benefits of aggressive local treatment of the primary tumor in metastatic urothelial carcinoma. Furthermore, our study identified important prognostic factors for mUTUC, including the number of metastatic organs and primary tumor site. These factors should be taken into account when designing effective treatment plans for patients with mUTUC. Overall, our results have important clinical implications and suggest that future randomized controlled trials should further investigate the potential benefits of aggressive local treatment in mUTUC.

SEER = Surveillance, Epidemiology and End Results, CRS = cytoreductive surgery, mUTUC = metastatic upper tract urothelial carcinoma.

ETHICS APPROVAL AND CONSENT TO PARTICIPATE

Not applicable

CONSENT FOR PUBLICATION

Not applicable

AVAILABILITY OF DATA AND MATERIALS

The datasets generated or analyzed during this study are available in the Surveillance, Epidemiology and End Results (SEER) repository, https://seer.cancer.gov/.

COMPETING INTERESTS

The authors have no relevant financial or non-financial interests to disclose.

FUNDING

The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

AUTHOR CONTRIBUTIONS

Haopu H., S. L. wrote the manuscript writing. M. W., C. L., and X. T. collected the data. Q. W., K. X., Haopu H. and S. L. analyzed the data. Hao H. and T. X. helped design the study and revise article. All authors have read and approved the manuscript.

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No competing interests reported.

Efficacy of Cytoreductive Surgery for Metastatic Upper Tract Urothelial Carcinoma: A Surveillance, Epidemiology and End Results (SEER) study of 508 patients

Status:

Journal Publication

Version 1

Abstract

Objective

Material and Methods

Results

Conclusions

Figures

INTRODUCTION

MATERIALS AND METHODS

Population

Description of covariates

Statistical Analysis

RESULTS

Patient’s Characteristics

Survival analysis based on CRS

Subgroup analysis based on different adjuvant treatment

DISCUSSION

CONCLUSIONS

Abbreviations

Declarations

References

Additional Declarations

Status:

Journal Publication

Version 1