Association of Comorbidities with Survival in Elderly Patients with Metastatic Bladder Cancer Treated with Chemotherapy


 IntroductionBladder cancer has a high incidence in elderly patients who have complex comorbidities. There are no data on the association between the comorbidities and overall survival (OS) of elderly patients with metastatic bladder cancer treated with chemotherapy; therefore, we evaluated the comorbidities of these patients.MethodsWe retrospectively reviewed the data of stage IV bladder cancer patients > 65 years of age who underwent chemotherapy at the Busan Paik Hospital between 2008 and 2018. The comorbidities were assessed using the Cumulative Illness Rating Scale-Geriatric.ResultsWe retrospectively reviewed the data of 22 patients. The median age at diagnosis was 71.5 years. The most common comorbidities were genitourinary and hematopoietic diseases. The median OS of all patients was 23.9 months (95% confidence interval: 4.9–42.8). Based on the univariate and multivariate analyses of the prognostic factors associated with OS, no comorbidity categories were found to be associated with OS.ConclusionsAlthough this was a small, retrospective, single-center study, no comorbidity categories were associated with OS. We should not hesitate to treat elderly patients with metastatic bladder cancer, and we should always evaluate their comorbidities in clinical practice.


Introduction
Bladder cancer is the ninth most common cancer worldwide and the 10th most common cancer in South Korea [1,2]. Its incidence rates increase in patients older than 65 years of age, and the highest rates are found in patients aged 75-84 years Elderly patients have complex comorbidities, functional impairments or mobility disabilities, and geriatric syndrome. The comorbidities of elderly patients with cancer in uence the treatment, survival, cancer risk, and recurrence [3][4][5][6]. The evaluation of the comorbidities of elderly patients with cancer is important to determine the process of management. Although most patients with bladder cancer treated with chemotherapy are elderly people, there are no data regarding the association between their comorbidities and survival. Therefore, this study aimed to evaluate the comorbidities of elderly patients with bladder cancer treated with chemotherapy and to analyze the comorbidities associated with survival.

Materials And Methods
We retrospectively reviewed the data of stage IV bladder cancer patients > 65 years of age who underwent chemotherapy at the Busan Paik Hospital between 2008 and 2018. The comorbidities were assessed using the Cumulative Illness Rating Scale-Geriatric (CIRS-G), which includes 14 organ categories and grades each comorbidity according to severity (score of 0-4) [7,8]. The following clinical data were obtained: demographics (age and sex), Eastern Cooperative Oncology Group performance status (ECOG PS), site of metastasis, previous treatment, MAX2 index, and adverse events (AEs). The MAX2 index describes the overall risk of the severe toxicity of a regimen with the highest frequency of both grade 4 hematologic toxicity and grade 3-4 non-hematologic toxicity and shows the correlation with the overall risk of severe toxicity by ECOG trials. AEs were graded according to the National Cancer Institute Common Terminology Criteria for AEs ver. 4.0 [9,10]. All data were collected from the electronic medical records of the Busan Paik Hospital. We analyzed the associations of the comorbidities, overall survival (OS), and AEs using the Cox proportional hazard regression model. All data analyses were conducted using SPSS version 25. All p-values were two-sided, and a p-value < 0.05 was deemed statistically signi cant. This study was approved by the Institutional Review Board of the Busan Paik Hospital (IRB No.20-0164).

Patient characteristics
The data of 22 patients were evaluated. The patients' characteristics are listed in Table 1. The median age at diagnosis was 71.5 years. Most patients (81.8%) were male, and 81.9% had an ECOG PS of 0 or 1.
Most of the sites of metastasis (54.6%) were the lymph nodes. Ten (45.5%) patients had previous surgery. The median MAX2 index score of chemotherapy was 0.285. The median number of chemotherapy cycles administered was 4.
The treatment-related AEs are summarized in Table 2. All-grade hematologic AEs occurred in 19 patients, ve of whom had a CIRS-G score of 3. The most common hematologic AE was anemia (N = 9, 40.9%). Three patients had grade 4 neutropenia, and one patient had grade 4 febrile neutropenia. Table 2 Adverse events in all patients Non-hematologic toxicity of all grades, n (%) 2 (9.1)

OS
The median OS of all patients was 23.9 months (95% con dence interval: 4.9-42.8) (Fig. 3). Based on the univariate and multivariate analyses of prognostic factors, no categories were found to be associated with OS (Table 3).

Discussion
This is the rst retrospective study conducted to evaluate the association between the comorbidities and survival of elderly patients with metastatic bladder cancer treated with chemotherapy in South Korea. The median OS of all patients was 23.9 months. No categories of comorbidities or clinical factors were associated with OS. Many studies have shown that comorbidities are associated with survival and cancer treatment [11][12][13][14]. In a previous study, the comorbidities were evaluated using the Charlson Comorbidity Index (CCI), which showed that cancer survival and treatment are associated with the CCI grade. However, in this study, the comorbidities were evaluated using CIRS-G, which showed the associations of each category with the survival of patients who underwent chemotherapy. Although no comorbidity categories were associated with survival, two studies showed that each category is associated with the survival of elderly patients with cancer [15,16]. The most common comorbidities were genitourinary and hematopoietic diseases. The categories of a CIRS-G score of 3 were hematopoietic and upper GI diseases, while there were no categories for a CIRS-G score of 4.
All patients underwent gemcitabine and platinum chemotherapy. Therefore, the median MAX2 score was 0.285. The most common AEs of chemotherapy were grade 1-2 hematologic toxicities, which most commonly includes anemia and thrombocytopenia. One patient had a grade 4 febrile neutropenia. All patients tolerated gemcitabine combined with platinum chemotherapy.
This study had several limitations. It was a small, retrospective, single-institution study. The median OS of 23.9 months was longer than that in the current population. Selection bias was a possible cause associated with survival. The small population limited the evaluations of the association of comorbidities with survival and toxicities. In addition, we did not routinely evaluate the comorbidities in our hospital, as the electronic medical records were insu cient to provide these data. However, this study is the rst to show the association between the comorbidities and survival of elderly patients with metastatic bladder cancer treated with chemotherapy, showing that no comorbidity categories were associated with survival. Thus, we should not hesitate to treat elderly patients with metastatic bladder cancer, and we should always evaluate their comorbidities in clinical practice.

Data availability
Data are available upon request.  Distribution of the total CIRS-G score.

Figure 3
Kaplan-Meier estimates of the overall survival.