Lung Metastases Versus Second Primary Lung Cancers in Patients with Primary Urothelial Carcinoma of the Bladder: A National Population-Based Assessment

INTRODUCTION

At the time of a new bladder cancer diagnosis, it is common to discover indeterminate lung lesions on staging imaging. These findings may represent the presence of metastatic bladder cancer or a second primary lung cancer. These difficult clinical conundrums usually require further diagnostic pursuit, potentially including a biopsy or interval imaging. This subsequent evaluation may delay definitive treatment which is critical to good outcomes in aggressive bladder cancer [1, 2]. An additional consideration is how diagnosing a second primary cancer may also lead to considerable changes in the original bladder cancer treatment plan.

In general, cancer survivors are at an increased risk of developing second primary malignancies, particularly when cancers share common risk-factors, such as tobacco use [3]. An estimated 712,000 bladder cancer patients in the US will be at risk for second cancers as survival increases with improved bladder cancer treatments [4]. Timely diagnosis of second malignancies is critical for improving survivorship and decreasing morbidity and mortality from secondary disease [5].

Unfortunately, despite the causal link between smoking and both lung and bladder cancer [6– 8], the comparative incidence of metastatic bladder and synchronous second primary cancers is poorly quantified as is the timing and incidence of metachronous lung cancers after a diagnosis of bladder cancer. We hypothesize that there is an underappreciated risk of second primary lung cancers at both the time of diagnosis and long term for adults with bladder cancer. Therefore, the aim of this study is to use a national, population-level dataset to evaluate and compare the rates of metastatic bladder cancer with synchronous and metachronous lung cancers to help inform patient counseling and guide clinical decision making.

METHODS

RESULTS

DISCUSSION

Using a large population-based cancer registry we determined that in adults with MIBC, there is a roughly five times greater incidence of lung metastases from bladder cancer (3.9%) than synchronous second primary lung cancers (0.7%) near the time of diagnosis. This information may help inform the decision making process when weighing the risks and benefits of further diagnostic evaluation of lung masses at the time of MIBC diagnosis. Accordingly, among adults with NMIBC, we found a similar incidence of bladder cancers metastatic to the lung (0.3%) compared with synchronous second primary lung cancers (0.4%).

The disparate rates of lung metastases for MIBC (3.9%) and NMIBC (0.3%) are likely the result of the biologic potential of more aggressive disease to spread wider in the body. However, the similar incidence of synchronous primary lung cancers regardless of bladder cancer stage (0.7% and 0.4%) may be due to either a true, similar risk of a second primary lung cancer, or may be related to differences in the approach to staging. Adults with NMIBC likely receive less intensive chest imaging (Chest X-Ray vs. Computed Tomography scan) than those with MIBC. This calls into question how variation in the utilization of lung imaging at bladder cancer diagnosis can influences detection rates and is an important potential area for subsequent research.

Another important finding of our study was quantifying the increased risk of metachronous second lung cancers among bladder cancer patients compared to a general population, particularly among individual age and gender subgroups. The increased SIR among younger adults (< 60) with both NMIBC and MIBC may support efforts that selectively screen this high-risk group of bladder cancer survivors for lung cancer. Timely diagnosis of second malignancies is critical for improving survivorship and decreasing morbidity and mortality from secondary disease [5]. Alternatively, the higher risk of subsequent lung cancers in younger adults may be related to a competing risk of mortality from bladder cancer or other causes in the elderly.

Although most previous studies have been in small cohorts or have focused on non-muscle invasive bladder cancer (NMIBC) and the incidence of second cancers [13– 15], our findings are similar to data from French cancer registries on 11,000 patients diagnosed with bladder cancer with SIRs for lung cancer of 3.12 and 3.27 for men and women, respectively [16]. Our data demonstrated higher SIRs among females across tumor stage and time to lung cancer development, with the highest rate 7.5 for synchronous lung cancers in females with MIBC. This is in contrast to historical data and higher rates of lung and bladder cancer in men [17]. These data are also consistent with prior SEER registry data from 1993 – 2002 that found an SIR of 1.71 for second lung cancers after NMIBC [14]. Although this study found a cumulative 15-year incidence of 8.8% compared to 4.3% expected, the study did not include MIBC patients or designate a difference in the risk of synchronous versus metachronous disease. A separate case series from Spain suggest a 10-fold higher rate of second lung cancers at a median interval occurrence of 54.2 months in NMIBC patients [13]. This contrasts with data from Kwon et al. who did not find increases in overall second lung cancers after bladder cancer diagnosis [18].

Cancers of the bladder and lung share a common causal etiology [7] and recognition of their connection is underappreciated. In addition to these data, prior work has shown a pronounced risk of second primary cancers within the first 2-3 years after cancer diagnosis [19], suggesting that a more complete upfront staging for NMIBC may be warranted. Furthermore, one tumor registry indicates worse survival in patients diagnosed with both cancers when bladder is diagnosed before lung (17 vs. 42 months) [20]. In a separate small series, lung cancer was the cause of death in all 10 patients who developed both NMIBC and lung cancer [13], indicating lung cancer drives mortality when both cancers are diagnosed. This highlights the potential for guidelines to include staging protocols that specifically assess for lung cancer in high-risk patients. A second primary lung cancer could change the overall treatment approach for a patient with bladder cancer who may have otherwise been treated locally for NMIBC or with systemic chemotherapy for presumed metastatic muscle invasive bladder cancer. Further studies are warranted to determine if intensive lung cancer screening can improve outcomes for patients with NMIBC. Screening protocols could be tailored to higher risk groups based on age, gender, smoking risk, and interval from initial cancer diagnosis. Regular screening for lung cancer could also serve as additional opportunities for urologists to engage in targeted screening efforts and smoking cessation education for bladder cancer patients who continue to smoke.

Limitations of the data include the lack of smoking information or subsequent metastatic bladder cancer risk in our analysis, as these variables are not available in the SEER dataset. Smoking could potentially confound the development of secondary lung cancers among this group as suggested by work by Shiels et al. that reported increased rates of second cancers among bladder cancer patients with a trend toward higher rates relative to current versus former smoking and magnitude of cigarettes smoked per day [21]. Prior work on second cancers in the SEER dataset [22] has not been able to define metastatic disease sites specifically as the ‘lung metastasis’ variable was not defined until 2010. A strength of our study is that we used more recent data after inclusion of this variable, allowing us to differentiate between metastatic bladder cancer to the lung and true primary second lung cancers. However, even though all included diagnoses were histologically confirmed, there still remains a risk of misclassification.

Additionally, we lack detailed information on the extent or intensity of staging imaging (e.g. CT or chest x-ray) which could cause ascertainment bias. Guideline recommendations for chest imaging are only well defined for muscle invasive bladder cancer (MIBC) and the detection of metastatic disease. Screening and detection of secondary primary cancers is not well defined. Neither the European Association of Urology (EAU) nor the American Urologic Association (AUA) mentions chest imaging in the NMIBC guideline [23, 24]. Similarly, the National Comprehensive Cancer Network (NCCN) bladder cancer guideline does not recommend chest imaging for NMIBC, but does recommend imaging for MIBC with preference for chest CT stated at the end of the guideline [25]. Therefore, the lesser intensity of imaging use among NMIBC patients may have biased our findings towards lower detection rates. Furthermore, some data suggests that indeterminate lung nodules in patients with non-pulmonary cancer can be benign in up to 10– 58% of cases, with a higher risk for a second primary cancer or metastatic lesion associated with higher pack-years, and nodule number and size [26, 27]. This further highlights the need for refined diagnostic pathways for defining metastatic lesions among bladder cancer patients regardless of disease stage.

Lastly, we did not adjust for bladder cancer treatment type, as patients who receive systemic chemotherapy or radiation may be at higher risk for second cancers than those treated with surgery or intravesical therapy alone. This lack of adjustment likely had minimal effect given the majority of the patients had NMIBC (77%), in agreement with accepted provenances for non-invasive disease [28], a group who typically does not receive systemic chemotherapy or radiation.

CONCLUSION

In summary, we have demonstrated that all patients with bladder cancer, regardless of tumor stage, have an increased risk of synchronous and metachronous lung cancers compared to matched adults in the general population. However, among adults with MIBC, a lung nodule is more likely to be metastatic bladder cancer than a second lung primary. These findings provide data that may help inform decision making on a frequent clinical conundrum and should encourage further multi-institution assessment using data that allows adjustment for smoking status and different lung screening protocols among bladder cancer survivors.