Abstract
Background
Comorbidity alterations during neoadjuvant chemotherapy (NAC) in patients with muscle invasive bladder cancer (MIBC) are not well studied. Comorbidity-estimates are mainly based on calculations at diagnosis. It is unknown if comorbidities alter in this patient group. This study aimed to investigate if comorbidity alterations during treatment need to be considered, for scientific evaluations.
Methods
A retrospective study of comorbidity alterations on MIBC patients undergoing NAC using age adjusted Charlson Comorbidity Index (CACI). We identified 684 patients between 2007–2022 from four Swedish cystectomy centers, a total of 320 were enrolled in the study. Inclusion criteria were nondisseminated MIBC, cT2–4aN0M0, NAC-treatment or NAC-eligibility. Medical files were reviewed and CACI were assessed and graded at three checkpoints during treatment: At diagnosis, post-NAC and pre-surgery. The cohort was divided into three subgroups, NAC complete, NAC incomplete and NAC-eligible. Data was retrospectively analyzed in SPSS Statistics 29.0 using descriptive statistics, one-way analysis of variance (ANOVA) and t-test.
Results
The total cohort (n=320) had an increase in CACI, 0.11 CACI points, between diagnosis and prior to surgery [95% confidence interval (CI): 0.06–0.15, P<0.001]. The NAC-incomplete group had the highest increase in CACI, 0.21 CACI points from diagnosis to pre-surgery (95% CI: 0.03–0.39, P=0.01). The NAC-complete group also had an increase in CACI, 0.11 CACI points from diagnosis to pre-surgery (95% CI: 0.06–0.15, P<0.001). The NAC-eligible group had no significant CACI-alterations. The most common events causing an increase in CACI was suspected peptic ulcer (85.2%).
Conclusions
There is a statistically significant increase of comorbidity in the total cohort as well as for two of the three subgroups, the NAC complete group and the NAC incomplete group. However, the increases are subtle and of limited clinical significance. This suggests that regardless of adverse events, complications, or progression, comorbidities only slightly change over time in the patient group. All together, answering the primary question if a comorbidity measurement at any moment on the timeline is sufficient.
Keywords: Urinary bladder neoplasms, neoadjuvant therapy, cystectomy, comorbidity
Highlight box.
Key findings
• Comorbidity constants post-neoadjuvant chemotherapy and pre-cystectomy do not alter significantly in muscle invasive bladder cancer-patients.
What is known and what is new?
• This aspect has not been studied previously, neither retrospectively nor prospectively in this specific group of patients.
• The investigation adds new knowledge in this field, especially for retrospective research on a database.
What is the implication, and what should change now?
• Future investigations can use either timepoint for comorbidity evaluations.
Introduction
Urinary bladder cancer is the 10th most diagnosed cancer worldwide, the 6th most common in men and 17th most common in women (1). At the time of diagnosis, 20–25% of cases are muscle invasive bladder cancer (MIBC), clinical stages T2–T4. The standard curative treatment for clinically fit patients is neoadjuvant chemotherapy (NAC) prior to radical cystectomy (RC) when patients tolerability is expected to be better than after RC (2). Studies have shown an absolute risk reduction (ARR) of 31% in favor of NAC in complete responding patients (pT0N0M0) on 5-year overall survival. It also increases survival in patients who are not complete responders (3). When treated with RC alone, the 5-year survival of MIBC is 50% (4). NAC improves disease free survival by eradicating micro metastases (5).
When diagnosed with bladder cancer, patients undergo clinical staging through transurethral resection of bladder (TUR-B) and computed tomography (CT). Currently, this is also the time of stating patients’ comorbidities using the age adjusted Charlson Comorbidity Index (CACI). CACI is a commonly used assessment tool that predicts long time survival based on comorbidities and age (6-8). Analyzing comorbidities is performed to estimate if extensive surgery and NAC is possible. Finally, clinically fit patients diagnosed with MIBC (cT2–T4N0M0) undergo 3–4 cycles of NAC. Following this step is RC 4–8 weeks post-NAC (5).
The standard NAC-treatment is based on cisplatin. The recommended NAC in Sweden is a combination therapy consisting of high-dose methotrexate, vinblastine, adriamycin, and cisplatin (HD-MVAC), another option would be gemcitabine-cisplatin (GC). Both GC and HD-MVAC are comparable in downstaging and in long-term survival (5). Platinum compounds are known to cause side effects in organs such as the kidneys, lungs, heart, vascular system and in the bone marrow (9). While NAC improves survival, some patients cannot tolerate it and must terminate the treatment prematurely due to the side effects. These patients have a decrease in tumor downstaging. Tumor downstaging is considered being a robust surrogate marker for overall survival (9).
In summary, the side effects and ensuing possible comorbidity-changes after NAC-treatment are not well investigated. Currently, publications regarding comorbidities of the patient-group in focus, are based only on comorbidity at the time of diagnosis. It is not described how and if the comorbidity differs between time of diagnosis, after NAC-treatment or at the time of cystectomy. It is also unknown if comorbidities differ between the group that completes intended NAC and the group that does not. Therefore, the main purpose of this project was to investigate whether the CACI-score differs between the three checkpoints within each group. The second purpose was to find out if there was a difference between the groups. Altogether, answering if more than one comorbidity factor should be considered with MIBC patients undergoing NAC. Our main hypothesis was that there are differences on the timeline and during the clinical process. We present this article in accordance with the STROBE reporting checklist (available at https://tau.amegroups.com/article/view/10.21037/tau-2025-192/rc).
Methods
Ethical information
The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments, and was approved by the institutional review board of Etikprövningsnämnden (EPN) Umeå, Sweden (protocol code 2013/463-31M, date of approval: 3rd of June 2014). Patient consent was waived due to the study being retrospective, and therefore, no informed consent was required according to EPN.
Materials
This retrospective multicenter study of a clinical database consisted of patients from four Swedish cystectomy centers: Norrlands Universitetssjukhus (NUS), Gävle sjukhus (Region Gävleborg), Länssjukhuset Sundsvall/Härnösand (Region Västernorrland) and Västerås sjukhus (Region Västmanland) between the years 2007–2022. Inclusion criteria were patients with undisseminated urothelial MIBC, clinical categories; cT2–4aN0M0. Participants where either treated with NAC or retrospectively considered eligible for NAC. During this period a total of 684 patients were diagnosed with MIBC and treated with cystectomy at the four centers mentioned. A total of 320 patients were enrolled for analysis according to Figure 1.
Figure 1.
Flowchart displaying the exclusion and inclusion process resulting in 320 patients in the final analysis. IC, induction therapy; NAC, neoadjuvant chemotherapy; NAC-eligible non-NAC, patient group considered NAC eligible retrospectively but did not receive NAC; PET-CT, positron emission tomography-computed tomography.
Data collection
Data collection was performed retrospectively from medical records and compiled in a Microsoft Excel database. The database consisted in total of 684 individuals. Patients who did not receive NAC due to primary comorbidities or age were excluded from the analysis, according to the European Association of Urology (EAU) Guidelines (10). Patients who underwent a positron emission tomography-CT (PET-CT) during investigation were also excluded from the study, this for evaluating a more homogenous cohort that had undergone the same or similar diagnostic work-up and not adding a subgroup with enhanced cN-staging which might have affected our original goal of the study. A total of 321 patients were enrolled for analysis of which 260 received NAC. A total of 206 participants received ≥3 cycles, and were defined as NAC complete, while 54 participants received <3 cycles, and were defined as NAC incomplete. 61 participants did not receive any NAC but were considered eligible for NAC retrospectively. These participants were considered NAC-eligible if absent from contraindications (10). The contraindications considered were age >75 years, kidney-failure, CACI >7 and hearing impairment. The reason why the NAC-eligible patients had not received the treatment was due to introduction-delay of NAC for a number of years in Sweden. Twenty-three patients had missing data and were excluded from analysis (Figure 1).
Calculating CACI-score
The CACI-score was calculated individually at three checkpoints, after TUR-B, after finishing NAC and before RC (Table 1). The CACI was calculated using an age-adjusted online calculator, taking into consideration myocardial infarction, congestive heart failure, peripheral vascular disease, cerebrovascular infarction, dementia, chronic obstructive pulmonary disease, connective tissue disease, peptic ulcer disease, liver disease, diabetes mellitus, hemiplegia, chronic kidney disease, solid tumor (none, localized or metastatic), leukemia, lymphoma and acquired immunodeficiency syndrome (AIDS). In the case of a newly discovered event, e.g., suspected peptic ulcer disease debut during the observed period, the patient received an extra CACI point according to the severity of the event. We used MD+CALC for the CACI-calculations: Charlson Comorbidity Index (CCI).
Table 1. Timeline displaying the checkpoints of when the CACI score was calculated for each group (X indicates checkpoint).
| Patient categories | Timeline checkpoints | ||
|---|---|---|---|
| TUR-B | Post-NAC | Pre-RC | |
| NAC complete | X | X | X |
| NAC incomplete | X | X | X |
| NAC-eligible | X | X | |
The three checkpoints were at the time of TUR-B, after finishing NAC and pre-RC. Note that there were only two checkpoints in the NAC-eligible group. CACI, age adjusted Charlson Comorbidity Index; NAC, neoadjuvant chemotherapy; pre-RC, before radical cystectomy; TUR-B, transurethral resection of the bladder.
Statistical analysis
Standard descriptive statistics were used to conduct the mean CACI for the three groups with standard deviation (SD). Paired t-test was used to achieve differences in CACI together with confidence interval (CI) and P value within each of the three groups. Furthermore, at each time point, a one-way analysis of variance (ANOVA) was used to analyze the difference between the groups. The data was statistically evaluated in SPSS Statistics 29 for Mac (IBM Corporation, Armonk, NY, USA).
Results
Of the 320 patients, 205 received all pre-planned cycles and 54 terminated NAC prematurely with less than three cycles; 61 patients did not receive NAC but were considered eligible in retrospect due to absence of contraindications.
Baseline characteristic of the study cohort
All 320 patients underwent RC. Of the 320 patients 75.3% were men and the mean age was 68 years. A total of 201 patients (62.8%) received HD-MVAC while 37.2% received another regimen according to Table 2. The mean CACI for the 320 patients at TUR-B was 4.7, post NAC 4.9 and pre cystectomy 4.8.
Table 2. Baseline characteristics on the total study cohort (n=320) with three subgroups: NAC complete, NAC incomplete and NAC-eligible.
| Characteristic | Total cohort | NAC complete | NAC incomplete | NAC-eligible |
|---|---|---|---|---|
| Gender | ||||
| Male | 241 (75.3) | 152 (74.1) | 39 (72.2) | 50 (82.0) |
| Female | 79 (24.7) | 53 (25.9) | 15 (27.8) | 11 (18.0) |
| Total | 320 (100.0) | 205 (100.0) | 54 (100.0) | 61 (100.0) |
| Age (years) | 68±8 | 68±7 | 69±5 | 67±8 |
| BMI (kg/m2) | 26.3±4.0 | 25.9±3.8 | 26.6±4.6 | 27.1±4.3 |
| cT-stage | ||||
| T2 | 210 (66.9) | 130 (65.0) | 31 (58.5) | 49 (80.3) |
| T3 | 84 (26.8) | 55 (27.5) | 17 (32.1) | 12 (19.7) |
| T4a | 20 (6.4) | 15 (7.5) | 5 (9.4) | 0 (0.0) |
| Downstaging (pTNM) | ||||
| CR (pT0N0M0) | 103 (32.2) | 80 (39.0) | 12 (22.2) | 11 (18.0) |
| PR (pTa, pTis, pT1N0M0) | 50 (15.6) | 32 (15.6) | 12 (22.2) | 6 (9.8) |
| SD (pT2-4aN0M0) | 110 (34.4) | 63 (30.7) | 18 (33.3) | 29 (47.5) |
| PD (pN+, pT4b) | 57 (17.8) | 30 (14.6) | 12 (22.2) | 15 (24.6) |
| CACI | ||||
| At time of TUR-B | 4.7±1.1 | 4.6±1.1 | 5.2±1.2 | 4.7±1.0 |
| At time of post-NAC | 4.9±1.2 | 4.8±1.1 | 5.4±1.3 | No data |
| At time of pre-cystectomy | 4.8±1.2 | 4.8±1.1 | 5.4±1.3 | 4.7±1.0 |
| NAC regimen | ||||
| HD-MVAC | 201 (62.8) | 160 (78.0) | 41 (75.9) | – |
| HD-MVEC | 15 (4.7) | 12 (5.9) | 3 (5.6) | – |
| Carbo-Gem | 11 (3.4) | 8 (3.9) | 3 (5.6) | – |
| GC | 1 (0.3) | 1 (0.5) | 0 (0.0) | – |
| Other | 21 (6.6) | 18 (8.8) | 3 (5.6) | – |
| HD-MVAC and other | 4 (1.3) | 3 (1.5) | 1 (1.9) | – |
| HD-MVAC and Carbo-Gem | 4 (1.3) | 3 (1.5) | 1 (1.9) | – |
| Carbo-Gem and other | 1 (0.3) | 0 (0.0) | 1 (1.9) | – |
| Carbo-Gem, GC and other | 1 (0.3) | 0 (0.0) | 1 (1.9) | – |
Data are presented as n (%) or mean ± standard deviation. CACI, age adjusted Charlson Comorbidity Index; BMI, body mass index; Carbo-Gem, carboplatin-gemcitabine; CR, complete response; cT, clinical tumor; GC, gemcitabine-cisplatin; HD-MVAC, high-dose intensity methotrexate, vinblastine, adriamycin and cisplatin; HD-MVEC, high-dose methotrexate/vinblastine/epirubicine/cisplatin; NAC, neoadjuvant chemotherapy; PD, progressive disease; PR, partial response; pTNM, pathological tumor-node-metastasis; SD, stable disease; TUR-B, transurethral resection of bladder.
CACI alterations total cohort
Table 3 displays the difference in CACI, the results were conducted using a paired T-test. When analyzing the total cohort, an increase of 0.11 CACI points was observed from TUR-B to cystectomy (95% CI: 0.06–0.15, P<0.001). Additionally, an increase of 0.12 CACI points was observed from TUR-B to post-NAC (95% CI: 0.07–0.18, P<0.001). There was no significant difference in CACI between post-NAC and cystectomy. A one-way ANOVA test showed that the difference between TUR-B and pre-RC was dependent on subgroups (P=0.02).
Table 3. Difference in CACI within total cohort and subgroups.
| Group | Difference CACI mean | 95% CI | P |
|---|---|---|---|
| Total | |||
| Pre-RC—TUR-B | 0.11 | 0.06 to 0.15 | <0.001 |
| Post-NAC—TUR-B | 0.12 | 0.07 to 0.18 | <0.001 |
| Pre-RC—post-NAC | 0.0 | 0.0 to 0.1 | 0.16 |
| NAC complete | |||
| Pre-RC—TUR-B | 0.11 | 0.06 to 0.15 | <0.001 |
| Post-NAC—TUR-B | 0.11 | 0.06 to 0.15 | <0.001 |
| Pre-RC—post-NAC | 0.0 | 0.0 to 0.0 | No data |
| NAC incomplete | |||
| Pre-RC—TUR-B | 0.21 | 0.03 to 0.39 | 0.01 |
| Post-NAC—TUR-B | 0.19 | 0.01 to 0.38 | 0.02 |
| Pre-RC—post-NAC | 0.02 | −0.02 to 0.06 | 0.16 |
| NAC-eligible | |||
| Pre-RC—TUR-B | 0.02 | −0.2 to 0.05 | 0.50 |
| Post-NAC—TUR-B | No data | No data | No data |
| Pre-RC—post-NAC | No data | No data | No data |
Conducted using a paired t-test. CACI, age adjusted Charlson Comorbidity Index; CI, confidence interval; NAC, neoadjuvant chemotherapy; RC, radical cystectomy; TUR-B, transurethral resection of the bladder.
CACI alterations in subgroups
According to Table 3, the NAC complete group had an equal increase of 0.11 CACI points from TUR-B to pre-RC and from TUR-B to post-NAC (95% CI: 0.06–0.15, P<0.001). The NAC incomplete group had an increase of 0.21 CACI points from TUR-B to pre-RC (95% CI: 0.03–0.39, P=0.01) and an increase of 0.19 CACI points from TUR-B to post NAC (95% CI: 0.01–0.38, P=0.02). Neither NAC complete nor NAC incomplete had a significant difference in CACI from post-NAC to pre-RC. The NAC eligible group only had CACI data from TUR-B and pre-cystectomy, and therefore was only analyzed between these two checkpoints. However, there was no significant difference in CACI between the two checkpoints.
Causes of increased CACI
Out of the 320 patients, a total of 27 (8%) had an increase in CACI from the time of TUR-B to cystectomy according to Table 4. Out of these, a total of 23 (85.2%) patients suffered from suspected peptic ulcer or started peptic ulcer medication during the observed period. One patient was diagnosed with suspected peptic ulcer and heart failure, another patient was diagnosed with diabetes mellitus and another with metastatic disease.
Table 4. Reasons of increased CACI score.
| Subgroups | Diabetes mellitus | Metastatic disease | Suspected peptic ulcer | Suspected peptic ulcer and heart failure | Stroke | Total |
|---|---|---|---|---|---|---|
| NAC complete | 1 | 0 | 18 | 0 | 1 | 20 (74.0) |
| NAC incomplete | 0 | 1 | 5 | 1 | 0 | 7 (26.0) |
| NAC-eligible | 0 | 0 | 0 | 0 | 0 | 0 (0) |
| Total | 1 (3.7) | 1 (3.7) | 23 (85.2) | 1 (3.7) | 1 (3.7) | 27 (100.0) |
Data are presented as number or n (%). The diagnosis, peptic ulcer, was founded on symptoms. CACI, age adjusted Charlson Comorbidity Index; NAC, neoadjuvant chemotherapy.
Discussion
The results of this study show a statistically significant increase in CACI from TUR-B to post-NAC and from TUR-B to pre-RC in the total cohort as well as in two out of three subgroups: NAC complete and NAC incomplete. There was no statistically significant difference in CACI in the NAC-eligible group. However, the increase in CACI is subtle, ranging from 0.11 to 0.21 CACI points, which can be considered being of limited clinical significance. These results suggest that comorbidities only slightly change over time in patients undergoing NAC for MIBC. Regardless of adverse events, complications, or progression.
This answers the overall question of the study; it is not necessary to consider more than one comorbidity factor on this moving target group. Furthermore, no significant difference was detected between the patients who completed all NAC cycles and the ones that terminated NAC prematurely, which indicates that CACI is stable for both groups. Yet, we acknowledge that approximately 8% of the patients in the cohort actually did have increased CACI. Having a larger original cohort in future evaluations could be of value to investigate, for better understanding if that subset might have certain clinical data and clinical markers related to observed increased CACI.
The most common cause of increase in CACI points was suspected peptic ulcer disease, although few cases were verified with gastroscopy. Instead, most were put on medication as a preventive measure. According to the CACI calculator, if the patient has any history of medical treatment or ulcer bleeding, they earn a CACI point. This highlights the bluntness of CACI as a comorbidity calculator since it does not differentiate peptic ulcer treatment, e.g., proton pump inhibitors, a commonly used over the counter medicine, from a verified peptic ulcer bleeding. Other than suspected peptic ulcer disease a total of four patients had an increase of CACI, one patient was diagnosed with diabetes mellitus, one with metastatic disease, one with stroke and one with heart failure and suspected peptic ulcer disease. To our knowledge, no other similar study has been conducted to answer this question which makes it difficult to compare the results to other studies. However, Eriksson et al. (9) studied adverse events on the same group of patients, they discovered that the most common adverse events where anemia, thrombocytopenia and acute kidney failure. This differs greatly from the results of this study where the most common cause of CACI alterations were peptic ulcer disease, diabetes mellitus, stroke, heart failure and metastatic disease. However, it may be difficult to compare the results since adverse events and CACI are two separate variables. In the future, it could be interesting to analyze overall survival combined with CACI-alterations to see whether the former is affected by the latter.
Strengths and weaknesses
The strength of this study is the large number of patients (n=320) included from four cystectomy centers in Sweden. The weaknesses are firstly, that each cystectomy center has its own medical record system making it difficult to find the relevant data for each patient since the study is retrospective. Secondly, the CACI difference data is not normally distributed.
Conclusions
The current comorbidity calculation is acceptably stable during the observed period, and therefore it might not be necessary to consider more than one comorbidity calculation at any time, in MIBC-patients undergoing NAC for forthcoming scientific evaluations.
Supplementary
The article’s supplementary files as
Acknowledgments
None.
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 and its subsequent amendments, and was approved by the institutional review board of Etikprövningsnämnden (EPN) Umeå, Sweden (protocol code 2013/463-31M, date of approval: 3rd of June 2014). Patient consent was waived due to the study being retrospective, and therefore, no informed consent was required according to EPN.
Footnotes
Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tau.amegroups.com/article/view/10.21037/tau-2025-192/rc
Funding: This research was funded by the Swedish Research Council funding for clinical research in medicine (ALF) in Västerbotten, VLL (grant No. Bas-ALF/VLL RV-848051), and the APC was funded by A.S. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-2025-192/coif). A.S., the corresponding author, declares that he received (grant No. Bas-ALF/VLL RV-848051) as funding concerning this project from the Swedish Research Council funding for clinical research in medicine (ALF) in Västerbotten, VLL, Sweden. A.S. also received honorarium as PI for a trial from Bristol Myers Squibb, completely unrelated to this study. The other authors have no conflicts of interest to declare.
Data Sharing Statement
Available at https://tau.amegroups.com/article/view/10.21037/tau-2025-192/dss
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