Edited by: Jianfeng Liu, Huazhong University of Science and Technology, China
Reviewed by: Rosario Le Moli, University of Catania, Italy; Huy Gia Vuong, University of Oklahoma Health Sciences Center, United States
*Correspondence: Jing Tao,
This article was submitted to Cancer Endocrinology, a section of the journal Frontiers in Endocrinology
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Urinary bladder carcinoma is common in developed settings, and prognosis may be impacted by lifestyle factors such as excess body weight and diabetes mellitus. The present meta-analysis aimed to systematically collate and analyze evidence on the impact of diabetes and excess BMI on bladder cancer outcomes.
PubMed, Scopus, and Google Scholar databases were screened for relevant studies that examined the association between bladder cancer outcomes and diabetes and/or excess body weight. The primary outcomes for this study were mortality (both all-cause and cancer-specific), risk of cancer progression, and recurrence. Strength of association was presented in the form of pooled adjusted hazard ratios (HR). Statistical analysis was performed using STATA version 16.0.
Twenty-five articles met inclusion criteria. Nine of these examined diabetes mellitus while 16 studied body mass index. All studies were retrospective. Diabetic patients had significantly higher risk for all-cause mortality (HR 1.24, 95% CI: 1.07, 1.44, n=3), cancer specific mortality (HR 1.67, 95% CI: 1.29, 2.16, n=7), disease progression (HR 1.54, 95% CI: 1.15, 2.06, n=8), and recurrence (HR 1.40, 95% CI: 1.32, 1.48, n=8) compared to non-diabetics. No statistically significant risk change for all-cause mortality, cancer specific mortality, disease progression, and recurrence was found for overweight patients. However, obese individuals were at higher risk for disease progression (HR 1.88, 95% CI: 1.41, 2.50, n=3) and recurrence (HR 1.60, 95% CI: 1.06, 2.40, n=7) compared to normal BMI patients.
These findings suggest that diabetes and excess body weight negatively influences bladder cancer prognosis and outcome. The increased risk of mortality due to diabetes was similar to that in the general population. Since retrospective studies are potentially susceptible to bias, future prospective studies on this subject are required.
Urinary bladder cancer is quite prevalent, particularly in high-income settings (
Efforts have been made to predict prognosis in bladder cancer patients using scoring tables (
The literature search was designed and conducted based on PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) guidelines. We screened PubMed, Scopus, and Google Scholar academic databases for all English-language publications published prior to March 31, 2021. The search strategy incorporated medical topic heading (MeSH) terminology and free text words (
Study titles and abstracts were initially reviewed by two subject experts. Following this, the full texts for candidate studies were subsequently reviewed. Disagreements were resolved through discussion. Only studies that met all inclusion criteria were included for meta-analysis. Reference lists from included studies were manually screened for additional candidate studies.
Relevant data from included studies was extracted using a set form by two independent reviewers. Extracted data included identification details, study setting, study design, sample size, follow-up duration, and main findings. Study quality was assessed using the Newcastle-Ottawa Quality Assessment Scale (
This meta-analysis was conducted using STATA software (version 16.0) and reported effect sizes as pooled hazard ratios with 95% confidence intervals (CIs). Separate analyses were performed for diabetes and body mass index. Subgroup analysis was performed for tumor type (muscle invasive or non-muscle invasive), tumor stage, and tumor grade. I2 was used to denote heterogeneity. We used random effects model as the included studies were diverse in their characteristics i.e., study subjects, geography, ethnicity, tumor characteristics etc. (
Literature search revealed 789 candidate studies (
Study inclusion process.
Diabetic patients had significantly higher risks for both all-cause mortality (HR 1.24, 95% CI: 1.07, 1.44, n=3) and cancer-specific mortality (HR 1.67, 95% CI: 1.29, 2.16, n=7) than non-diabetics (
Relationship between diabetes and bladder cancer outcomes.
Subgroup analysis showed that all-cause mortality risk among diabetics with an advanced tumor stage (≥T2) (HR 1.25, 95% CI: 1.07, 1.47, n=2) was elevated (
Subgroup analysis for diabetes as a bladder cancer risk factor.
Pooled effect size (Hazard ratio; HR) (95% Confidence Interval) | ||||
---|---|---|---|---|
Stage of tumor | Grade of tumor | |||
Early stage (PTa or T1) | Advanced (≥T2) | Low | High | |
All-cause mortality | N=1 | N=2 | — | N=3 |
1.19 (0.81, 1.74) | 1.25 (1.07, 1.47) | 1.24 (1.07, 1.44) | ||
Cancer specific mortality | N=3 | N=3 | N=2 | N=4 |
1.43 (1.23, 1.66) | 1.58 (1.04, 2.39) | 1.96 (1.44, 2.67) | 1.39 (1.11, 1.76) | |
Risk of progression | N=5 | N=3 | N=3 | N=5 |
1.45 (1.16, 1.82) | 1.97 (0.59, 6.58) | 2.13 (1.00, 4.53) | 1.39 (1.09, 1.76) | |
Risk of recurrence | N=5 | N=3 | N=3 | N=5 |
1.39 (1.31, 1.48) | 1.54 (1.20, 1.97) | 1.34 (1.17, 1.55) | 1.41 (1.32, 1.51) |
Out of the 9 studies included in the meta-analysis, only one study had subjects with muscle invasive bladder. Similarly, in only one study, majority of the subjects had tumor size>3 cm; In all the studies, patients did not have >2 tumors and none of the studies reported presence of carcinoma in situ in majority of the subjects. The modality of treatment in almost all the studies was transurethral resection of bladder with/without adjuvant therapy. Therefore, due to lack of variation for these variables among the included studies, sub-group analysis was not conducted on these variables.
The risks of cancer-specific mortality (Low grade: HR 1.96, 95% CI: 1.44, 2.67, n=2; High grade: HR 1.39, 95% CI: 1.11, 1.76, n=4), disease progression (Low grade: HR 2.13, 95% CI: 1.00, 4.53, N=3; High grade: HR 1.39, 95% CI: 1.09, 1.76, N=5], and disease recurrence (Low grade: HR 1.34, 95% CI: 1.17, 1.55, n=3; High grade: HR 1.41, 95% CI: 1.32, 1.51, n=5) were elevated among diabetics with either low or high grade tumors. For all-cause mortality, risk was elevated only among diabetics with high grade tumors (HR 1.24, 95% CI: 1.07, 1.44, n=3) (
No statistically significant association was noted between BMIs classified as overweight and all-cause mortality (HR 1.05, 95% CI: 0.74, 1.49, n=4) relative to the relationship between normal BMIs and all-cause mortality. Likewise, no association was noted for cancer specific mortality (HR 0.92, 95% CI: 0.75, 1.13, n=6), disease progression (HR 1.45, 95% CI: 0.79, 2.66, n=3), or recurrence (HR 1.22, 95% CI: 0.80, 1.87, n=7) (
Bladder cancer patient outcomes in overweight and normal BMI patients.
Subgroup analysis showed a decrease risk of cancer-specific mortality for overweight individuals with muscle-invasive bladder cancer (MIBC) (HR 0.77, 95% CI: 0.67, 0.89, n=3) compared to normal BMI counterparts (
Subgroup analysis for bladder cancer outcomes in overweight patients relative to normal BMI.
Type of tumor | Grade of tumor | Stage of tumor | ||||
---|---|---|---|---|---|---|
Non-muscle invasive (NMIBC) | Muscle invasive (MIBC) | Low | High | Early stage (PTa or T1) | Advanced (≥T2) | |
All-cause mortality | N=2 | N=2 | N=1 | N=3 | N=2 | N=2 |
0.97 (0.63, 1.50) | 1.13 (0.69, 1.85) | 0.80 (0.69, 0.93) | 1.20 (0.91, 1.58) | 0.97 (0.63, 1.50) | 1.13 (0.69, 1.85) | |
Cancer specific mortality | N=3 | N=3 | N=1 | N=5 | N=2 | N=4 |
1.18 (0.95, 1.45) | 0.77 (0.67, 0.89) | 1.19 (0.91, 1.56) | 0.84 (0.70, 1.02) | 0.86 (0.49, 1.52) | 0.96 (0.75, 1.22) | |
Risk of progression | N=3 | — | N=1 | N=2 | N=3 | — |
1.45 (0.79, 2.66) | 1.36 (0.57, 3.24) | 1.45 (0.62, 3.40) | 1.45 (0.79, 2.66) | |||
Risk of recurrence | N=5 | N=2 | N=2 | N=5 | N=5 | N=2 |
1.48 (0.96, 2.26) | 0.80 (0.59, 1.09) | 1.42 (1.11, 1.81) | 1.15 (0.65, 2.03) | 1.31 (0.75, 2.29) | 0.95 (0.80, 1.14) |
Compared to patients with normal BMI, obese patients had elevated risk for disease progression (HR 1.88, 95% CI: 1.41, 2.50, n=3) and recurrence (HR 1.60, 95% CI: 1.06, 2.40, n=7). However, no statistically significant risk change was noted for all-cause mortality (HR 1.33, 95% CI: 0.85, 2.07, n=3) or cancer-specific mortality (HR 0.94, 95% CI: 0.54, 1.66, = 5) (
Bladder cancer patient outcomes in obese and normal BMI patients.
Subgroup analysis for bladder cancer outcomes in obese patients relative to normal BMI.
Effect size (Hazard ratio; HR) (95% Confidence Interval) | ||||||
---|---|---|---|---|---|---|
Type of tumor | Grade of tumor | Stage of tumor | ||||
Non-muscle invasive (NMIBC) | Muscle invasive (MIBC) | Low | High | Early stage (PTa or T1) | Advanced (≥T2) | |
All-cause mortality | N=1 | N=2 | — | N=3 | N=1 | N=2 |
0.97 (0.62, 1.52) | 1.57 (1.04, 2.36) | 1.33 (0.85, 2.07) | 0.97 (0.62, 1.52) | 1.57 (1.04, 2.36) | ||
Cancer specific mortality | N=2 | N=3 | — | N=5 | N=2 | N=3 |
1.51 (1.05, 2.16) | 0.68 (0.25, 1.84) | 0.94 (0.54, 1.66) | 0.74 (0.22, 2.42) | 1.26 (0.83, 1.91) | ||
Risk of progression | N=3 | — | N=1 | N=2 | N=3 | — |
1.88 (1.41, 2.50) | 3.04 (1.24, 7.44) | 1.79 (1.36, 2.37) | 1.88 (1.41, 2.50) | |||
Risk of recurrence | N=5 | N=2 | N=2 | N=5 | N=5 | N=2 |
2.01 (1.39, 2.90) | 0.94 (0.30, 2.96) | 1.45 (1.04, 2.01) | 1.65 (1.01, 2.76) | 1.57 (0.80, 3.08) | 1.66 (1.46, 1.89) |
The current meta-analysis aimed to examine the relationship between bladder cancer outcomes and diabetes or body weight. This study found that diabetic patients had significantly elevated risk for all-cause mortality, cancer specific mortality, disease progression, and recurrence. Obese patients also showed significantly elevated risk for disease progression and recurrence. However, no change in risk for all-cause mortality and cancer specific mortality was noted.
The deleterious influence of diabetes on cancer-related outcomes has been previously documented (
While the findings of the meta-analysis indicate that diabetes is associated with mortality, recurrence and tumor progression, there are many considerations to take into account. First and foremost, we did not explore whether there was a difference between the non-bladder cancer death risk and the bladder cancer death risk in diabetic patients as none of the included studies had non-bladder cancer subjects. Having this analysis would have been important to understand whether presence of diabetes increased the risk of mortality in subjects with bladder cancer, over and above the risk of mortality in the general population or subjects with no bladder cancer. Available evidence indicates that the risk of mortality due to diabetes in the general population is similar to the estimates from the current meta-analysis involving patients with bladder cancer. This may imply that presence of diabetes among subjects with bladder cancer does not significantly increase the risk of mortality, when compared to the general population. However, this finding should not be interpreted as lack of benefit in terms of survival among bladder cancer patients through efforts aimed at better glycemic control. Diabetes is a multifactorial disease where duration, glycosylated hemoglobin levels (HbA1c), glycemic variability, age of patients and sex constitute a cluster with very different impact on clinical peculiarity. In the included studies, majority of the participants had type 2 diabetes and were on oral hypoglycemics. The participants were usually aged more than 60 years of age and majority were males. A growing amount of evidence supports a link between obesity-associated inflammation and cancer incidence and progression (
This study highlights the need for close monitoring, supervision and follow up in urinary bladder cancer patients presenting with either elevated BMI and/or diabetes in order to alleviate the risk of mortality, recurrence and disease progression. This study did have several limitations. First, almost all included studies were retrospective, making it difficult to account for any adjustment for potential confounding factors. There is a need for future prospective studies on this issue in order to provide reliable and unbiased evidence. One of the obvious limitations of this meta-analysis is the lack of evidence synthesis on the association of glycemic control (using HbA1c) with the outcomes. This could not be done because of included studies not reporting this association. Further, this was not the primary analysis planned and future research should aim to explore this association. Another limitation relates to the inclusion of multicentric studies and the lack of information concerning protocol harmonization across centres. The study attempted to derive an association of diabetes and BMI with mortality, progression or cancer recurrence. However, it should be noted that a significant overlap between diabetes, obesity, insulin and hypoglycemic agents on cancer outcome could be a major cause of bias in this study. We did not find a statistically significant association between BMI classified as overweight and all-cause mortality. However, there is a limitation to it. There is no unique reference range/operational definition for BMI that was being used to categorize overweight in the included studies. Further, there is a difference in the reference range based on the gender of the participants. While it would have been useful to perform an adjunctive analysis according to sex and related BMI, such an analysis could not be done because of lack of reported gender specific findings in the studies included in the meta-analysis. Finally, retrospective studies largely assessed the presence or absence of diabetes based on medical records/treatment history, and this could result in bias concerning classification. Similarly, different studies used different cut-offs to define “overweight” and “obese”. These discrepancies may lead to inter-study heterogeneity.
The current meta-analysis suggests that both diabetes and excessive BMI can potentially negatively influence bladder cancer outcomes such as mortality, progression, and recurrence. The risk of mortality due to diabetes in patients with bladder cancer was similar to that in the general population. However, this finding does not undermine the need for better glycemic control in these patients in order to improve survival. Given that retrospective study designs may be subject to certain biases, there is a need for prospective studies investigating this relationship.
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.
YL conceived and designed the study. JT and YL did literature search, analysis and wrote the paper. YL reviewed and edited the manuscript. All authors contributed to the article and approved the submitted version.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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