Efficacy of cystectomy in single-site oligometastatic bladder cancer: a Surveillance, Epidemiology, and End Results (SEER) study of 1,381 patients

Introduction

Bladder cancer is the second most common genitourinary malignancy worldwide, with approximately 573,000 new cases and 213,000 new deaths in 2020 (1). Metastatic and unresectable disease account for about 10% of all newly diagnosed bladder cancer (2,3). The treatment paradigm of metastatic bladder cancer has remained largely unchanged over the past 20 or so years with cisplatin-based chemotherapy as the standard of care for first-line treatment, with 5-year survival of about 15% (4). The appearance of immunotherapy, targeted therapy and antibody-drug conjugates has not fundamentally changed the poor prognosis of bladder cancer (5,6).

Metastatic disease usually heralds a lack of benefit from local treatment. In fact, the presence of distant metastases is considered by most surgeons as a contraindication for any form of definitive local therapy. And the value of local surgery, especially cystectomy is always surrounded with controversy, mostly often out of palliative intent in cases with severe local symptoms, such as dysuria and pain.

Such idea is being increasingly challenged in recent years. For example, colon rectal cancer with liver metastasis, once believed hopeless, is now found to be curable among suitable patients in a multidisciplinary setting, with definitive surgery playing a pivotal role (7). Several retrospective researches report feasibility and oncological effect of local treatment in other urological cancers (8,9). It thus reminds us that the role of local surgery should be reassessed in patients with metastatic bladder cancer.

Oligometastatic cancer, first introduced in Hellman and Weichselbaum as a distinct cancer state between locally confined and systemically metastatic disease in 1995 (10), is a focus in recent years (11-13). Single-site metastatic bladder cancer, defined as metastatic site confined to bone, brain, liver, lung or distant lymph nodes (DLNs) only, represents a state of early oligometastatic disease. Moschini et al. found that surgery of the primary tumor site is associated with improved survival in patients with metastatic urothelial cancer, only in those with one metastatic site (14).

Hence, to address the clinical needs, we exploited data from the Surveillance, Epidemiology, and End Results (SEER) database of bladder cancer patients from 2010 to 2017 to analyze risk factors for survival in single site metastatic scenario and especially evaluate the value of cystectomy in this group of patients with limited metastatic burden. We present this article in accordance with the STROBE reporting checklist (available at https://tau.amegroups.com/article/view/10.21037/tau-24-586/rc).

Methods

Study design and patient selection

The current study data were extracted from the SEER-18 registry of the United States National Cancer Institute. The SEER database is the largest, population-based cancer dataset, covering approximately 28% of cancer patients in the United States (15). After 2010, it classified the metastatic site of patients, including bone, brain, liver, lung and DLNs. Our study was based on the SEER database, which allowed the extraction of data (SEER-Stat username: 23614-Nov2021).

To select eligible patients, the search was restricted to cases with the diagnosis of bladder cancer (location coded as C67.0–C67.9) and distant metastasis at the time of diagnosis (M1 disease by American Joint Committee on Cancer sixth edition tumor-node-metastasis staging system or derived SEER combined stage system) in the period between 2010 and 2017 from the SEER database by the SEER*Stat software (8.4.1).

Data were extracted to select patients who fulfilled the following characteristics: (I) bladder as the primary tumor site; (II) de novo metastatic disease; (III) complete data regarding local surgery [including cystectomy and transurethral resection of bladder tumor (TURBT)].

The exclusion criteria in our study were as follows: (I) multiple metastatic site; (II) unknown surgery of primary site; (III) unknown surgery of metastatic site; (IV) unknown or no chemotherapy; (V) unknown radiotherapy; (VI) unknown survival time; and (VII) unknown cause of death.

Only patients receiving chemotherapy were selected, as we believed surgery should always be performed on the basis of effective chemotherapy, and its tolerance indicated a better performance score and health status, which, to some degree, offsets the flaw of the lack of patients’ condition in SEER database. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013).

Study variables and endpoints

We enrolled the demographic, pathological and treatment-related variables, including gender, race, age at diagnosis, marital status, histology type, grade, distant metastatic site, surgery of primary site, surgery of lymph node, radiotherapy, etc.

Metastatic pattern was divided into five subgroups: bone, lung, liver, brain and DLNs. Marital status was divided into two subgroups: married, others. Histology types was divided into two subgroups: transitional cell carcinoma (TCC) and variant histology (VH) according to ICD-O-3. Pathological grading standard was evaluated according to the SEER database. Surgery of primary site was divided into three groups: no surgery, TURBT and cystectomy. Additionally, according to the availability of immune checkpoint inhibitors (ICIs) for bladder cancer, which was first approved in 2016, the study period was divided into ICIs era (before 2016) and non-ICIs era (after 2016).

The data for metastasis were identified at the time of diagnosis. The primary end point was 24 months cancer-specific survival (CSS), defined as the time from diagnosis till death due to bladder cancer within 24 months. The selection of CSS over overall survival (OS) was to further preclude the impact of patients’ health status on endpoints.

The study objective was to evaluate the impact of surgery on survival outcomes in single-site metastatic bladder cancer. Separate analyses were performed in the overall population and subgroups of each single metastatic site. Cohorts were defined by target organ (bone, brain, lung, liver, DLNs) and then stratified by local surgery received (no surgery, TRUBT or cystectomy).

Statistical analysis

Student’s t-test and Pearson’s Chi-squared tests were performed for continuous variables and categorical variables, respectively. The former was presented as the mean ± standard deviation, the latter as frequencies and their proportions. Survival estimation and comparison among different variables were performed using Kaplan-Meier (K-M) analysis and the parameters included mean survival time, median survival time as well as 95% confidence interval. The log-rank test was used to evaluate the significance of survival curve differences.

Univariate and multivariate Cox proportional hazards regression were conducted to analyze the risk factor of patients’ survival. A cut off of 0.2 was chosen to select risk factors in univariate Cox regression analysis for the following multivariate analysis. Variates considered important from clinical perspective but insignificant in univariate analysis was also included in multivariate analysis. Statistical significance was set at two-sided P<0.05. All of the statistical analyses were performed using IBM SPSS software (version 26.0). All the graphs were drawn with the help of GraphPad Prism 7.0.0.

Results

Baseline characteristics

A total of 1,381 eligible patients from 2010 to 2017 were included in our study cohort through the SEER database, with 336 female (24.3%) and 1,045 male (75.7%). The mean age of the whole group was 67.75±10.8 years. Among all patients with single site metastasis, the most common affected organ is bone (31.6%), followed by DLNs (30.7%), lung (24.7%), liver (11.5%) and brain (1.4%) in order (Table 1). The subgroup with brain metastasis was left unevaluated for limited sample size (n=20).

Entire population survival analysis

The overall 24-month CSS was 25.9%. CSS in patients treated with no surgery, TURBT and cystectomy were 22.3%, 24.8% and 36.6% (P<0.001), with median survival of 10, 12 and 16 months, respectively (Figure 1A). K-M curve showed that patients with DLNs metastasis exhibited more favorable prognosis than other sites, with a 24-month survival of 36.0%, much higher than bone (21.5%), brain (10.0%), liver (19.0%) and lung (22.7%), with median survival of 17, 11, 9.5, 8 and 12 months, respectively (P<0.001) (Figure 1B).

Figure 1 Cancer-specific survival in patients with single-site metastatic bladder cancer. Kaplan-Meier survival curve for all patients with different treatment modality (A), patients of various metastatic sites (B). TURBT, transurethral resection of bladder tumor; DLNs, distant lymph nodes.

Univariate and multivariate Cox regression analyses indicated that cystectomy was associated with a protective effect on CSS [hazard ratio (HR) =0.60; P=0.001], compared with patients treated with no surgery. TURBT also seems to confer survival benefit, however without statistical significance (HR =0.85; P=0.12).

Compared with DLNs metastasis, visceral metastasis exhibited worse survival, including bone (HR =1.43; P<0.001), lung (HR =1.43; P<0.001), liver (HR =1.86; P<0.001) and brain (HR =2.17; P=0.002). Other significant risk factors included age (HR =1.01; P=0.001), T stage (T4, compared to ≤ T2, HR =1.37; P<0.001), race (others, compared to White, HR =0.62; P=0.005), history of malignancy (HR =1.29; P=0.002) and ICI era (HR =0.78; P=0.001) (Table 2).

Bone metastasis

Bone metastasis was found to be the most frequent metastatic site in single-site metastatic scenario. K-M curve revealed a better survival in patients receiving cystectomy, with median survival of 15 months, higher than that of both no surgery and TURBT (11 months), however, without statistic significance (P=0.01) (Figure 2A). Univariate and multivariate Cox regression found cystectomy (HR =0.58; P=0.03), rather than TURBT (HR =0.95; P=0.76), as an independent protective factor in patients with bone metastasis. Additionally, even when compared directly, TURBT was inferior to cystectomy with regard to survival (HR =1.62; P=0.03).

Figure 2 Cancer-specific survival for patients with bone (A), lung (B), liver (C) and DLNs (D) stratified by local treatment strategies including cystectomy, TURBT and no surgery; (E) cancer-specific survival for patients of different ICIs era. TURBT, transurethral resection of bladder tumor; DLNs, distant lymph nodes; ICIs, immune checkpoint inhibitors.

Lung metastasis

K-M survival curve found no significant survival difference in patients with different treatment strategies (Figure 2B). Multivariate Cox regression found cystectomy (HR =0.84; P=0.58) to be a potential protective factor, which fail to achieve statistical significance. ICIs era was the only survival protective factor, with HR of 0.69 (P=0.01).

Liver metastasis

K-M survival curve exhibited significantly different survival among three groups (P=0.03) (Figure 2C). The value of TURBT and cystectomy was further partly validated in multivariate Cox regression, with HR of 0.58 (P=0.06) and 0.40 (P=0.07) compared to no surgery, both on the verge of statistical significance, which may be due to limited sample, as only 10 patients received cystectomy. When TURBT and cystectomy was coalesced into one group, it exhibited an obvious survival benefit over chemotherapy alone (HR =0.57; P=0.04). Another unexpected discovery was that ICI era failed to prolong the survival in patients with liver metastasis (HR =0.93; P=0.74), suggesting insensitivity to immunotherapy in those patients.

DLNs metastasis

DLNs patients exhibited the best survival in single site metastatic scenario. K-M curve revealed a median survival of 14, 16 and 21 months for patients receiving chemotherapy, TURBT and cystectomy, respectively (P=0.007) (Figure 2D). Multivariate Cox regression analysis indicated cystectomy as an independent protective factor compared to chemotherapy (HR =0.51; P=0.005). In addition, cystectomy was found to be superior than TURBT in survival benefit, even when compared mutually (HR =0.65; P=0.01). We also found that VH had a negative impact on patients’ survival.

ICI era

With immune-checkpoint inhibitor’ approval in the treatment of urothelial cancer in 2016, the prognosis of metastatic bladder cancer experienced a drastic improvement. In our study, K-M curve found ICI era to be superior to non-ICI era with respect to survival, with median survival of 13 versus 11 months, 24-month OS of 28% versus 20% (P<0.001) (Figure 2E). Multivariate Cox regression confirmed ICI-era as an independent protective factor, with HR of 0.78 (P=0.01), indicating the reduction of death risk by 22%. In addition, subgroup analysis indicated that the survival benefit conferred by cystectomy was greater in ICI era than that in non-ICI era, with HR of 0.46 versus 0.61, respectively, in comparison to that of no surgery.

Discussion

To the best of our knowledge, this is the first population-based study targeting solely single-site metastatic bladder cancer. Although less common in clinical practice than non-muscle-invasive or muscle-invasive bladder cancer, the treatment of metastatic bladder cancer is a much tougher task for urologist. Platinum-based chemotherapy remains the standard of care treatment as the first line therapy, with immuno-checkpoint inhibitors and the newly approved antibody-drug conjugate as alternatives. However, the prognosis remains poor (16,17).

Oligometastatic disease represents an early stage of advanced malignancy, as well as the transitory stage between localized disease and widespread metastasis. With the in-depth knowledge of biological characteristics of malignancies and better understanding of its development pattern, there does exist a special subgroup of patients with metastatic disease, who could realize a rather long term of disease control. A prominent feature of those patients is limited metastatic sites, i.e., oligometastatic state. The concept of oligometastatic malignancy differs in different cancers, and has not been fully clarified in bladder cancer up to now (18-21).

Traditionally, local treatment of metastatic malignancy, irrespective of oligometastatic or poly-metastatic disease, was exclusively done out of palliative intent. However, with development of microinvasive surgery and radiation technology, the value of local treatment is being reevaluated in recent years (22-24). Colon rectal cancer with liver metastasis is found to be curable. Esophageal cancer with lung metastasis is also treated with synchronous surgical removal by some thoracic surgeon, which could confer survival benefits over systemic therapy only (21,25). The resection of metastasis is also revisited. Several studies found local therapy valuable in patients with limited metastasis (18,21,26).

We believe that systemic therapy should still be the backbone of oligometastatic disease. Its aim is to prevent disease progress, eliminate potential and undetected micro-metastasis and clarify the biological characteristics of certain malignancy. In a rapidly progressive scenario, local therapy is almost valueless, often resulting in more harm than good. Only under effective systemic treatment and disease control can we ponder the necessity of local therapy of primary tumor, which must take into account patients’ conditions, tumors’ characteristics and availability of medical options. Last, local treatment of metastasis such as metastasectomy or local radiation should not outweigh that of primary lesion. As primary tumor usually exhibits higher degree of malignancy, its treatment should also precede that of metastasis, except in patients with obvious metastasis-related symptoms. Several clinical trials regarding local treatment for metastasis were all conducted based on effective local control of primary site (22,27).

The reason why local treatment confers survival benefit in a metastatic disease, we believe, is that it improved the efficacy of systemic therapy and remedies its limitation, i.e., insufficient local control. Just as systemic therapy influences the survival of malignancy, the existence of malignancy may affect the efficacy of systemic therapy. The pathological complete response rate induced by neoadjuvant therapy was as high as more than 37% in patients with localized bladder cancer. However, in metastatic scenario, the response rate was still high, but cannot translate into survival benefit (28). A possible mechanism is that heavy circular tumor burden has a negative impact on the efficacy of systemic therapy, likely through secreted inhibitory cytokines (29). Immunity affects the development of malignancy and vice versa. In such case, removal of primary could theoretically restore normal immune response and thus improve the efficacy of systemic therapy. Another possible explanation is that the removal of primary hypermetabolic malignancy could ameliorate patients’ nutritional status, and thus further improve treatment tolerance and systemic immunity.

While our study focused on cystectomy, the role of radiation should not be neglected. As another kind of local therapy, radiation is an integral component of the trimodality therapy (TMT) bladder-preservation strategy. It was also found to be effective in oligometastatic and oligoprogressive bladder cancer (30). Radiation is less invasive than radical surgery, rendering it more accessible to those patients intolerant of surgery, which needs further exploration.

In comparison with previous studies published on this topic, our report has several strengths. First, it is the first study targeting solely single-site metastatic bladder cancer, indicating a state of oligometastasis. We truly believe that such patients are the only ones that may receive local treatment out of the intent for survival benefit. Second, our multivariable model adjusted some most important confounders regarding bladder cancer. For example, age, immunotherapy and presence of histological variants play an important role in determining survival outcomes in bladder cancer patients, and should be taken into consideration in survival models. Third, we divide local surgery into less invasive transurethral surgery and radical procedure of cystectomy according to clinical practice. From mutual comparison, we confirm cystectomy to be superior than transurethral surgery in patients with DLNs and bone metastasis. In liver metastatic scenario, it remains unclear which option is better, maybe due to limited sample size, with cystectomy exhibiting a tendency of survival superiority.

Our study is not devoid of limitations. First and most important of all, patients’ conditions and comorbidity status remain unknown, which not only affect the decision-making regarding treatment strategy but also OS. However, all selected patients received chemotherapy, the tolerance of which suggests a reasonable health status and offset to some extent the lack of health status. In addition, we chose CSS over OS as the primary endpoint, further precluding the impact of confounders. Second, some treatment details such as chemotherapy protocols or the adoption of ICIs remain unclear. Third, the choice of surgery is dependent on many factors. Operative indication varies across every patient. However, the reason for local therapy is not available in the SEER database. Multi-center, large-scale, prospective study is imperative to define the concept of oligometastatic disease and clarify the role of local surgery in the treatment of oligometastatic bladder cancer.

Conclusions

Cystectomy in the setting of multimodality protocols may prolong survival in bladder cancer patients with single-site metastasis of bone and DLNs. It should be considered in a multidisciplinary setting. Our results need to be validated in a prospective trial of patients who meet the selection criteria.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tau.amegroups.com/article/view/10.21037/tau-24-586/rc

Peer Review File: Available at https://tau.amegroups.com/article/view/10.21037/tau-24-586/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-24-586/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013).

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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