Development and validation a model for predicting overall survival of bladder cancer with lung metastasis: a population-based study

Cancer is not only the leading cause of death but is also the most important barrier to increased life expectancy in the world. Bladder cancer (BCa) is the tenth most common form of cancer globally, with an estimated 573,278 new BCa patients occurring in 185 countries during 2020, with 212,536 of these cases dying as a result of the tumor [1]. BCa included several subtypes such as urothelial carcinoma, squamous cell carcinoma, and adenocarcinoma. Among these, urinary bladder urothelial carcinoma was the major common histological subtype. Untreated metastatic bladder carcinoma has a poor prognosis, with the median survival time rarely exceeding 3 to 6 months [2].

Bladder carcinoma metastases include several patterns such as lymph node involvement (25.4%) and distant organ metastasis including bone (24.7%), brain (3.1%), liver (18.1%), and lung (19.4%). However, distant organ metastasis in BCa is considered a unique situation and although occurring rarely has an important significance as it is associated with significantly shortened survival [3‐7]. Unfortunately, approximately 10–15% of BCa patients are diagnosed with distant metastases at the time of the initial diagnosis, with up to 30% of patients with high-grade BCa eventually developing metastases that lead to a poor prognosis [8]. BCa with distant metastases can be treated with immunotherapy and systemic chemotherapy, resulting in 5-year survival rates of 36% for regional metastasis and 5% with distant metastasis [9]. The overall survival (OS) rate of BCa patients with metastases remains quite low despite multiple therapeutic modalities. For this reason, it is essential to construct prognostic models for OS of BCa patients with lung metastasis, as identifying patients with evaluated poor survival outcomes may guide enhanced therapeutics and improve prognosis [10].

According to a previous analysis of the Surveillance, Epidemiology, and End Results (SEER) database, up to 38.9% (724/1862) of BCa patients with distant metastasis had lung metastases [11]. Considering the rarity of lung metastases at presentation, there are currently no randomized clinical trial that have investigated the outcomes of this group.

However, we are aware of a few studies on metastatic BCa that have focused on the prognostic significance of lung metastasis from BCa detected at de novo diagnosis. Prognostic nomograms are currently used widely in oncologic medicine as prognostic devices. Because the knowledge of the prognosis of lung metastasis is essential for pretherapeutic assessment the aim of the current study was to describe the frequency of occurrence based on the SEER database. Another aim of the study was to construct a nomogram to predict OS in de novo diagnosed patients with BCa and lung metastasis. The study may also help to choose suitable management strategies by increasing the understanding of prognosis in newly diagnosed patients with BCa and lung metastasis.

To our knowledge, a considerable number of BCa patients have metastases at distant organs at diagnosis, leading to a shorter OS. Of the metastatic BCa organs, bone is the most common, followed by the lung. Bianchi et al. [4] also showed that the bone metastasis rate was higher than the lung metastasis rate in patients with M1 stage bladder cancer. A previous study studied the independent prognostic factors of outcome in BCa patients with bone metastasis [13]. However, the independent predictive factors of outcome in lung metastasis BCa still remain unknown. The aim of the present research was therefore to determine the independent predictive factors in BCa patients with lung metastasis and develop a predictive nomogram to help predict outcome risks.

Univariate and multivariate analyses were carried out in the current study on a large number of BCa patients with lung metastasis. These analyses showed that age at diagnosis, primary site of the tumor, histology, surgery of the primary site, additional chemotherapy, bone metastasis, and liver metastasis were independent prognostic factors for OS in BCa patients with lung metastasis.

The nomogram we constructed enables more personalized risk prediction and is a well-studied intuitive statistical model based on the results of a multivariate analysis [14, 15]. The integration of multiple independent prognostic factors in the model could further improve its accuracy to appraise the survival probability of an individual patient [16]. To date, several nomograms have been developed for different tumor types and have shown powerful predictive ability that is more accurate than the traditional TNM systems [17]. More importantly, clinicians are able to intuitively evaluate the physical condition of patients and offer individual predictions using nomograms. However to our knowledge before the current study there was no prognostic nomogram model for BCa patients with lung metastasis. Therefore, it is of great prognostic significance for these patients to establish a reliable and efficacious prognostic nomogram and to offer individualized therapies.

The present study investigated and validated a new prognostic tool based on the results of multivariate Cox regression models that included the age at diagnosis, primary site of the tumor, histology, bone metastasis, liver metastasis, chemotherapy, and surgery of the primary site. This tool enhanced prediction of OS in BCa patients with lung metastases. The results of the study demonstrated that the prognostic tool could be used to divide the patients into two groups (low-risk and high-risk) with wide variations in OS. Using a median cut-off value, the patients were divided into either high-risk or low-risk groups. We also assessed the accuracy of the 1- and 3-year OS in the prognostic nomograms, with the results indicating good consistency and reliability. In terms of its content, the prediction model is simple and easy to understand. First, in the nomogram, a vertical line is drawn from each clinicopathological parameter to the ‘points’ line, followed by addition of the score to determine the ‘total points’. A vertical line is then drawn from ‘total points’ to ‘1- or 3-years survival’. Based on the above analysis we are able to calculate the 1- or 3-year survival rates in lung metastatic BCa patients. For example, a 65-year-old male patient was diagnosed with a transitional cell carcinoma located in the lateral wall of bladder, without liver or bone metastases, and had undergone a TURB and chemotherapy. According to the nomogram, the ‘total points’ was 95 and the 1- and 3-years survival rates were approximately 45% and 20%, respectively.

In general, the prognostic factors identified in our study were associated strongly with the choice of therapeutic approach, as well as the metastatic site of the BCa patients. Previous research in BCa patients has demonstrated that a single metastatic site was capable of independently predicting better OS compared with multisite organ metastasis [17]. The results of our research were consistent with this previous study in that it showed better survival with lung metastases compared to a coalesced tumor or simultaneous bone metastasis or liver metastasis.

Treatment of BCa patients with lung metastases is not uniform. In the current study, we included five variables in the treatment of lung metastasis BCa, including surgery of the primary site, surgery of lymph nodes, surgery of other sites, radiation, and chemotherapy.

A previous study revealed that the primary site of surgery might contribute to long-term OS survival in lung metastatic BCa patients. Wang et al. [18] reported that the survival rates of metastatic BCa patients with adenocarcinoma and transitional cell (non)-papillary carcinoma could be improved by surgery of the primary site alone, while the survival rates of metastatic BCa patients with squamous cell carcinoma could be increased only by surgery combined with adjuvant chemotherapy. They also demonstrated that surgery of the primary site alone was an independent predictive factor of outcome, and that surgery could affect the OS of BCa patients with lung metastasis. We found that BCa patients with lung metastasis could also benefit from primary site surgery. Regarding surgery of lung metastasis, the conclusions remain limited due to a lack of consistent reports. However, there is evidence that a pulmonary metastasectomy, combined with chemotherapy may improve OS [19]. Although the efficacy of therapeutic approaches is susceptible to the underlying emergence of drug resistance, as shown in our nomogram, chemotherapy still has the greatest survival benefit for BCa patients with lung metastasis. This finding is consistent with the first-line treatment regimen in the guidelines of the European Urological Association [20]. Besides, in cancer, fibroblast growth factor receptors (FGFRs) have emerged as a novel therapeutic target [21]. As an oncogenic driver in bladder cancer, FGFR3 genomic alterations represent predictive biomarkers that predict the response to FGFR inhibitors. According to research, 50% of bladder cancers have somatic mutations of the FGFR3 gene [22, 23]. Bladder cancer is typically associated with FGFR3 gene rearrangements [24, 25]. While platinum-based chemotherapies have always been the main therapeutic approach for urothelial bladder carcinoma, the advent of antiFGFR-target therapy represents significant advances for bladder cancer patients with FGFR altered.

To our knowledge this is the first cohort study to investigate the risk factors for the prognosis of BCa with lung metastasis. Furthermore, the study is the largest cohort study to examine the prognostic significance of lung metastasis in BCa patients and to determine the effect of numerous treatment modalities on the prognosis of these patients. Nevertheless, we acknowledge that our study has several limitations. First, the retrospective research design of the study limited its conclusions and it was not possible to completely rule out confounding factors, such as smoking history etc. In addition, information on cancer recurrence was lacking, and patients who might have developed distant metastases later in their disease process were not taken into consideration.

Age at diagnosis, primary site of the tumor, histology, surgery of the primary site, additional chemotherapy, bone metastasis, and liver metastasis are independent predictive factors of outcome in BCa patients with lung metastasis. Based on these prognostic factors, we constructed a prognostic nomogram, which could provide the best assessment of OS and indicate appropriate therapy in BCa patients with lung metastasis.