Impact of sarcopenia in bladder preservation therapy for muscle-invasive bladder cancer patients: a narrative review

Introduction

Bladder cancer is the second most common genitourinary malignancy worldwide, with approximately 573,000 new cases and 212,000 deaths from bladder cancer in 2020 (1). Based on the stage, bladder cancer is divided into two categories: non-muscle-invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC). MIBC is more biologically aggressive than NMIBC and accounts for approximately 25% of all bladder cancer cases. Radical cystectomy (RC) with urinary diversion and lymph node dissection has been the gold standard treatment in MIBC patients (2). However, RC is an invasive and complex procedure and has considerable rates of complications that can cause bowel, urinary, and sexual dysfunctions. Moreover, these functional changes worsen quality of life (QOL) of patients (3). According to a systematic review of perioperative outcomes after robot-assisted RC, a 30-day overall complication rate, major complication rate, and mortality rate were 44%, 11.8%, and 1.6%, respectively (4).

Most MIBC patients are diagnosed beyond the age of 65, indicating that they can have poor general health status, many comorbidities, and frailty (5). Recently, sarcopenia, the degenerative and systemic loss of skeletal muscle mass, has gained interest in the management of cancer-bearing patients as an indicator of frailty (6,7). It can be caused by multiple etiologies such as advanced age, lack of physical activity, poor nutritional status, inflammatory diseases, endocrine disorders, neuromuscular diseases, and malignancies (8). A previous epidemiological study showed a high frequency of sarcopenia in the older population, with 13–24% at 65–70 years and over 50% at 80 years or older (9). The number of sarcopenic population is expected to reach 1.2 billion by 2025 and it will have doubled by 2050 (10). A growing number of studies showed that sarcopenia had a negative impact on prognosis in various cancers including lung or gastrointestinal cancer (11), esophageal cancer (12), gastric cancer (13), head and neck cancer (14) upper tract urothelial cancer (15), prostate cancer (16), and kidney cancer (17). Moreover, sarcopenia is associated with intolerance to cancer treatment and a higher rate of perioperative complications (18,19). For bladder cancer, sarcopenia is a significant predictor of worse cancer-specific survival (CSS) and a higher rate of perioperative complications in patients undergoing RC, suggesting that sarcopenic patients could be potentially unfit for RC (20-23). In addition, sarcopenic patients have poor prognosis in advanced disease treated with an immune checkpoint inhibitor (ICI) (24).

Bladder preservation therapy, which is generally called as ‘trimodal therapy’ and comprised of transurethral resection of the bladder tumor (TURB), chemotherapy, and radiotherapy, is an alternative therapeutic option in appropriately selected MIBC patients and those unfit or unwilling for RC (2,25). Bladder preservation therapy showed excellent long-term outcomes especially in appropriately selected patients with favorable clinical features such as small, solitary, and non-metastatic diseases, the absence of hydronephrosis, and the absence of extensive carcinoma in situ (26-28). Moreover, patients treated with bladder preservation therapy maintain good QOL after treatment (29,30). Given its less invasiveness compared with RC, bladder preservation therapy may be fit for sarcopenic MIBC patients. In this study, we summarized the definitions of computed tomography (CT)-determined sarcopenia and reviewed the literature on the impact of sarcopenia on oncological outcomes and complication rates in MIBC patients treated with bladder preservation therapy. We present this article in accordance with the Narrative Review reporting checklist (available at https://tau.amegroups.com/article/view/10.21037/tau-22-355/rc)

Definitions of CT-determined sarcopenia

CT-determined sarcopenia can be easily and objectively evaluated with a high reproducibility (31). Thus, CT scan is generally used in the evaluation of sarcopenia in many clinical studies. To evaluate sarcopenia, the total skeletal muscle area at the third lumbar spinal level is measured using axial CT slices (32,33). The cross-sectional area of the psoas, paraspinal muscles (the erector spinae and quadratus lumborum), and abdominal wall muscles (the transversus abdominus, external and internal obliques, and rectus abdominus) is identified using Hounsfield unit range of −29 to +150. Next, skeletal muscle index (SMI) is calculated by normalizing the measured skeletal muscle area for height in meters squared. Three major definitions of sarcopenia have been used in most previous papers on CT-determined sarcopenia (34). In 2008, Prado et al. firstly reported a CT-determined definition of sarcopenia: SMI <52.4 cm²/m² for men and <38.5 cm²/m² for women (Prado’s definition) (35). In 2011, the International definition was proposed by a panel of international experts: SMI <55 cm²/m² for men and <39 cm²/m² for women (36). In 2013, Martin et al. proposed a body mass index (BMI)-incorporated definition of sarcopenia: SMI <43 cm²/m² for males with BMI <25 kg/m², <53 cm²/m² for males with BMI ≥25 kg/m², and <41 cm²/m² for females (Martin’s definition) (11).

Moreover, only the psoas muscle area was quantified on axial CT scans at the lumbar vertebral level in many previous studies (37,38). Normalizing the psoas muscle area for height in meters squared yields the psoas muscle index (PMI). Several PMI-based definitions of sarcopenia have been proposed. Hamaguchi et al. defined sarcopenia as PMI <6.36 cm²/m² for males and <3.92 cm²/m² for females (37). Moreover, Japan Society of Hepatology proposed a definition of sarcopenia as follows: PMI <6.0 cm²/m² for males and <3.4 cm²/m² for females (38).

Methods

To investigate the effect of sarcopenia on oncological outcomes and complication rates of bladder preservation therapy in MIBC patients, the PubMed and Scopus databases were used to perform a literature review (Table 1). There were no restrictions on publication years. The following keywords were searched: ‘muscle-invasive bladder cancer’ and ‘bladder preservation therapy’ and ‘sarcopenia’; ‘muscle-invasive bladder cancer’ and ‘trimodal therapy’ and ‘sarcopenia’. Literature search was conducted independently by HF and FK. Consensus was obtained by opening discussion. Review articles were excluded. Finally, we included two studies that reported the impact of sarcopenia on responses to trimodal therapy and survival outcomes of bladder preservation therapy in MIBC patients and two studies that compared complication rates of bladder preservation therapy between MIBC patients with and without sarcopenia.

In this section, based on the result of our literature search, we review and discuss the oncological outcomes and perioperative complications of bladder preservation therapy in MIBC patients with sarcopenia.

Impact of sarcopenia on the oncological outcomes of bladder preservation therapy against MIBC

Two papers reported responses to trimodal therapy and survival outcomes of bladder preservation therapy in MIBC patients with or without sarcopenia (Table 2). Almarzouq et al. showed the oncological outcomes of trimodal therapy, including TURB, chemotherapy [cisplatin alone (weekly at a dose of 40 mg/m²), or gemcitabine alone (weekly at a dose of 100 mg/m²)], and radiotherapy (total dose: 44–66 Gy), using a cohort of 141 MIBC patients (39). They defined sarcopenia using the two definitions: the International and Martin’s definitions. Sarcopenia was observed in 56.7% and 40.4% of the total patients using the International and Martin’s definitions, respectively. Associations between sarcopenia and other clinicopathological parameters were evaluated using Student’s T or Wilcoxon Rank test for continuous variables and Chi-Square or Fisher’s exact test for categorical variables. In both definitions, sarcopenic patients were significantly older and had worse performance status compared with non-sarcopenic patients. Complete response (CR) rates to trimodal therapy in sarcopenic and non-sarcopenic patients were 72.5% and 75.4%, respectively, according to the International definition (P=0.51) and 75.4% and 72.6%, respectively, according to the Martin’s definition (P=0.62). Moreover, sarcopenia by the International definition was significantly associated with overall survival (OS) in univariate analysis (P=0.035) but not in multivariate analysis (P=0.66) using the Cox proportional hazards model. Similar results were obtained for sarcopenia by the Martin’s definition; it was significantly associated with OS in univariate analysis (P=0.025) but not in multivariate analysis (P=0.19) using the Cox proportional hazards model. Tanaka et al. compared the oncological outcomes between sarcopenic and non-sarcopenic patients in 126 MIBC patients treated with tetramodal therapy, which includes TURB, chemotherapy [2 cycles of intravenous cisplatin (20 mg/body) for 5 days], radiotherapy (total dose: 40 Gy), and consolidative partial cystectomy with pelvic lymph node dissection (40). The inclusion criteria were as follows: pathologically confirmed urothelial carcinoma, circumscription within ≤25% of the bladder surface, the absence of the bladder neck involvement, and the absence of broad carcinoma in situ. In addition, consolidative partial cystectomy was performed only in patients with a clinical CR to trimodal therapy, which was confirmed by urine cytology, magnetic resonance imaging, and tumor site re-biopsy. A robotic-assisted laparoscopic approach was not used in consolidative partial cystectomy. Sarcopenia was diagnosed with 54.0% of the total patients using the Martin’s definition. No significant associations were observed between sarcopenia and other clinicopathological parameters using Mann-Whitney U test for continuous variables and Fisher’s exact test for categorical variables. CR rates to trimodal therapy were 85.3% and 81.0% in sarcopenic and non-sarcopenic patients, respectively (P=0.52). In 90 patients who completed consolidative partial cystectomy, survival outcomes were equivalent between 49 sarcopenic and 41 non-sarcopenic patients. Five-year MIBC-recurrence-free survival (RFS) was 97% (P=0.96) and 5-year CSS was 94% (P=0.96) in both sarcopenic and non-sarcopenic patients using the Kaplan-Meier method.

Impact of sarcopenia on perioperative complication rates of bladder preservation therapy against MIBC

Tanaka et al. reported complication rates in consolidative partial cystectomy using a cohort of MIBC patients treated with tetramodal therapy including TURB, chemotherapy, radiotherapy, and consolidative partial cystectomy with pelvic lymph node dissection (Table 3) (40). Total complication rates (Clavien-Dindo 1–5) are 22.4% and 46.3% in sarcopenic and non-sarcopenic patients, respectively (P=0.02). Moreover, the rates of Clavien-Dindo 3 complications that included bladder-anastomotic leaks, lymphoceles, and postoperative hemorrhage were 4.1% and 12.2% in sarcopenic and non-sarcopenic patients, respectively (P=0.24). There were no Clavien-Dindo 4–5 complications in either group. Fraisse et al. showed complication rates of trimodal therapy using 29 MIBC patients (Table 3) (41). The radiotherapy protocol consisted of two sequences of daily hypofractionated irradiations for a total dose of 20 to 80 Gy. The dose per fraction ranged from 2 to 20 Gy. A tumor boost of 12 to 70 Gy and a lymph node boost of 44 Gy were performed in four and two patients, respectively. Sarcopenia was observed in 13 (44.8%) patients based on the Martin’s definition. Total complication rates (Clavien-Dindo 1–5) were 90.9% and 56.3% in sarcopenic and non-sarcopenic patients, respectively. Major complication rates with Clavien-Dindo 3–5 were reported to be 45.5% and 6.3% in sarcopenic and non-sarcopenic patients, respectively.

Discussion

Previous studies reported that sarcopenia was significantly associated with worse prognosis and a higher complication rate in bladder cancer patients undergoing RC (20-23). This suggests that sarcopenic patients could be potentially unfit for RC. Meanwhile, two previous studies reported that sarcopenia did not affect the oncological outcomes of bladder preservation therapy against MIBC. Tanaka et al. showed equivalent CR rates to trimodal therapy between sarcopenic and non-sarcopenic patients (40) Moreover, in patients undergoing partial cystectomy after trimodal therapy, sarcopenia was not associated with lower 5-year MIBC-RFS or CSS. Because this study used the strict inclusion criteria to assure the oncological safety (pathologically confirmed urothelial carcinoma, circumscription within ≤25% of the bladder surface, the absence of bladder neck involvement, and the absence of broad carcinoma in situ), excellent survival outcomes might be yielded regardless of the presence of sarcopenia. In addition, because bladder preservation therapy is less invasive compared with RC, bladder preservation therapy might be more preferable rather than RC in MIBC patients with sarcopenia. Similarly, in the study reported by Almarzouq et al., CR rates to trimodal therapy were comparable between sarcopenic and non-sarcopenic patients (39). Moreover, sarcopenia was not an independent predictor of OS. As inclusion criteria for bladder preservation therapy were not specified in their study, these results would be insufficient to evaluate whether bladder preservation therapy can be a standard of care for sarcopenic patients or not.

Tanaka et al. reported that complication rates of consolidative partial cystectomy are comparable between sarcopenic and non-sarcopenic patients (40). This result would be attributed to less invasiveness of partial cystectomy compared with RC. Only Fraisse et al. reported complication rates of trimodal therapy in MIBC patients with sarcopenia (41). Sarcopenic patients showed higher rates of total and severe complications compared with non-sarcopenic patients. However, their cohort included only 29 patients and thus it is mandatory to validate their results in a larger cohort of trimodal therapy.

Recently, the advent of ICIs has shifted the paradigm of bladder cancer treatment (42). Currently, there are several ongoing clinical trials of bladder preservation therapy that combines TURB, chemoradiotherapy, and ICIs (43,44). ICIs can enhance abscopal effects by augmenting anti-cancer immunity in combination with radiotherapy or chemoradiotherapy (45,46). Thus, the use of ICIs may expand the indication of bladder preservation therapy including MIBC patients with metastatic lesions. This suggests that more sarcopenic patients with cancer cachexia might seek bladder preservation therapy. Given that chemotherapy is toxic in sarcopenic patients (19), other immunogenic therapy such as near-infrared photoimmunotherapy rather than chemoradiotherapy may be suitable for sarcopenic patients in combination with ICIs (47,48). Because sarcopenia was associated with poorer therapeutic efficacy of ICIs (24), further evaluation is necessary to determine the significance of sarcopenia in the management of bladder preservation therapy in the ICI era.

This study has several limitations. First, this study included only three articles and thus the sample size was limited. Second, all the included studies used a single method of measuring skeletal muscle mass. Still, multiple definitions of sarcopenia based on SMI was analyzed, Third, detailed data about patient characteristics and complications were not reported in all the included studies. Finally, all the included studies had limited follow-up period that may impact oncological outcomes.

In conclusion, sarcopenia appears not to affect responses to trimodal therapy and prognosis in MIBC patients treated with bladder preservation therapy. Because of limited evidence, it is unclear whether sarcopenia increases complication rates of bladder preservation therapy or not. Still, given its less invasiveness compared with RC, bladder preservation therapy could be a viable alternative in carefully selected MIBC patients regardless of the presence of sarcopenia. Further studies are necessary to elucidate whether bladder preservation therapy can be a standard treatment in MIBC patients with sarcopenia.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://tau.amegroups.com/article/view/10.21037/tau-22-355/rc

Peer Review File: Available at https://tau.amegroups.com/article/view/10.21037/tau-22-355/prf

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-22-355/coif). HF serves as an unpaid editorial board member of Translational Andrology and Urology from May 2022 to April 2024. FK has no conflicts of interest to declare.

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.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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