Spotlight on frailty in bladder cancer
Is frailty an underestimated marker in clinical practice?
Perioperative and long-term functional and oncological outcomes following radical cystectomy (RC) for bladder cancer remain unchanged, despite advances in technique and perioperative management as well as neoadjuvant therapy. Is there something we overlooked? The article below gives an overview of what we know so far about frailty and RC.
High rates
The RC procedure represents an integral component in the management of advanced bladder cancer. However, it is associated with high rates of postoperative morbidity (up to 90%) (1) and mortality rates between 0.8–8.3% (2). Patients suitable for RC are usually characterised as elderly and frail. They often suffer from other urgent medical conditions because of a heavy comorbid burden that should mandate pre-evaluation before scheduled surgery (3).
Frailty is defined as a syndrome of physiologic decline and loss of functional reserve across organ systems, leading to vulnerability for disease and death (4). Specific to RC, frailty is associated with higher complication rates and mortality (5).
Useful for clinical practice
The increased likelihood of pre and postoperative frailty calls for increased awareness to inform early risk assessment and qualify the shared decision process. However, most institutions performing RC do not routinely measure frailty in clinical practice. This could partly be explained by the absence of consensus on how to define and measure frailty in the urological community, despite a plethora of instruments, tools and scales according to the literature (6). Finally, there seems to be little agreement on which of those tools are useful for clinical practice. Thus, there is currently no standard recommendation of the optimum tool for measuring frailty in RC.
Frailty is a dynamic phenomenon and seems to be modifiable while patients – according to most scales – can move between the status of being robust to pre-frail and frail. One well-known tool is the Fried Frailty Phenotype (7), which defines frailty by the following criteria: impaired grip strength, gait speed, physical activity, unintentional weight loss and self-reported exhaustion. It seems to promote the concept of prehabilitation to modify or optimise deficits.
Sarcopenia
An important and fundamental component of frailty is sarcopenia, which is defined by progressive and severe loss of skeletal muscle mass. A common method of assessing sarcopenia in RC patients is measuring psoas muscle volume on preoperative abdominal imaging. This is already done prior to surgery to determine disease stage and is thus easy to access for clinical use.
However, standard cut-off values of psoas muscle volume for determining when patients are ‘frail’ (and thus at increased risk for postoperative complications and/or should change treatment direction) are yet to be established; they are warranted to facilitate early prevention of sarcopenia in clinical practice (4).
Sarcopenia is, however, accepted as an important preoperative prognostic factor of overall and cancer-specific survival after RC (8) and is associated with increased 30-day and 90-day high-grade complications (9-11). These findings support the association of certain components of the Fried Frailty Criteria with increased complications and stress the significant impact of preoperative physical fitness and nutritional status on postoperative outcomes of RC.
The physical decline including aerobic fitness and nutritional status are significant drivers in sarcopenia. Older patients, such as RC patients, who’s average age peaks around 67, are less able to utilise amino acids for protein synthesis at the muscle level, and almost 30% are at nutritional risk ahead of surgery (12,13). In addition, it is estimated that one-third of patients undergoing RC is sarcopenic and would benefit from a combined intervention of physical exercises and nutrition with protein supplements to attenuate the loss of lean leg mass and strength and promote the recovery phase (10, 14).
Prehabilitation
Today, it is generally accepted that exercises provide the best anabolic stimulus and nutrition potentiates the muscle protein response. Moreover, these two components are synergistically related. Therefore, a combined intervention should be offered in both the perioperative period and post-discharge to counteract sarcopenia, maximise recovery and reduce long-term impairments (14).
Although prehabilitation is not yet considered as standard treatment or is not offered due to concerns over a delay in cystectomy, this intervention may be a valuable preventive approach to modify well-known risk factors. Attempts to counteract frailty using multimodal prehabilitation programmes, including physical exercises and nutrition supplementation, have shown to be feasible, effective and lead to a positive change in patients’ fitness and functional status (12, 15, 16).
Frailty assessment
Both retrospective and prospective studies using a preoperative frailty assessment have shown that frailty is associated with worse outcomes. Preoperative frailty assessments, based on patients’ physiological fitness using the Fried Frailty Criteria or psoas muscle volume, have been the best predictors of worse outcomes on prospective cohorts (6). Perioperative risk assessment before RC should incorporate objective measures of physiologic age, physical function, nutrition, lean muscularity, cognitive age, patient preferences and frailty. Future work is needed to validate the performance of existing statistics to improve the ability to predict perioperative complications and oncologic outcomes and to define and assess the effectiveness of specific prehabilitation interventions to counteract deconditioning in relation to surgery.
Key points to consider in radical cystectomy in clinical practice
• Frailty is associated with worst postoperative outcomes after radical cystectomy.
• Frailty can be assessed using a frailty index or preoperative frailty assessment.
• Prospective studies show that preoperative assessments based on patients’ physiologic fitness and nutritional status are likely to be most useful for radical cystectomy.
• Further research is needed comparing various frailty assessments to determine the best tool for clinical practice.
• Inclusion of preoperative frailty assessment in guidelines for muscle-invasive bladder cancer is warranted to improve implementation in clinical care.
(From: Frailty and preoperative risk assessment before radical cystectomy. Burg, M L et al, Curr Opin Urol 2019, 29:216–219.)
References
1. Elmussareh M, Simonsen PC, Young M, Kingo PS, Jakobsen JK, Jensen JB. Correlation between organspecific co-morbidities and complications in bladder cancer patients undergoing radical cystectomy. Scandinavian Journal of Urology. 2018;52(5-6):395-400.
2. Banerjee S, Semper K, Skarparis K, Naisby J, Lewis L, Cucato G, et al. Patient perspectives of vigorous intensity aerobic interval exercise prehabilitation prior to radical cystectomy: a qualitative focus group study. Disabil Rehabil. 2019:1-8.
3. Psutka SP, Barocas DA, Catto JWF, Gore JL, Lee CT, Morgan TM, et al. Staging the Host: Personalizing Risk Assessment for Radical Cystectomy Patients. European urology oncology. 2018;1(4):292-304.
4. Burg ML, Clifford TG, Bazargani ST, Lin-Brande M, Miranda G, Cai J, et al. Frailty as a predictor of complications after radical cystectomy: A prospective study of various preoperative assessments. Urol Oncol. 2019;37(1):40-7.
5. Chappidi MR, Kates M, Patel HD, Tosoian JJ, Kaye DR, Sopko NA, et al. Frailty as a marker of adverse outcomes in patients with bladder cancer undergoing radical cystectomy. Urol Oncol. 2016;34(6):256.e1-6.
6. Grimberg DC, Shah A, Molinger J, Whittle J, Gupta RT, Wischmeyer PE, et al. Assessments of frailty in bladder cancer. Urol Oncol. 2020.
7. Fried LP, Tangen CM, Walston J, Newman AB, Hirsch C, Gottdiener J, et al. Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci. 2001;56(3):M146-56. 8. Mayr R, Gierth M, Zeman F, Reiffen M, Seeger P, Wezel F, et al. Sarcopenia as a comorbidity-independent predictor of survival following radical cystectomy for bladder cancer. Journal of cachexia, sarcopenia and muscle. 2018;9(3):505-13.
9. Wan F, Zhu Y, Gu C, Yao X, Shen Y, Dai B, et al. Lower skeletal muscle index and early complications in patients undergoing radical cystectomy for bladder cancer. World journal of surgical oncology. 2014;12:14.
10. Mayr R, Fritsche HM, Zeman F, Reiffen M, Siebertz L, Niessen C, et al. Sarcopenia predicts 90-day mortality and postoperative complications after radical cystectomy for bladder cancer. World J Urol. 2018;36(8):1201-7.
11. Smith AB, Deal AM, Yu H, Boyd B, Matthews J, Wallen EM, et al. Sarcopenia as a predictor of complications and survival following radical cystectomy. The Journal of urology. 2014;191(6):1714-20.
12. Bente Thoft Jensen GD, Jørgen Bjerggaard Jensen, Caitlyn Retinger Mallory Bowker. Implementing a Multimodal Prehabilitation Program Prior to Radical Cystectomy in a Comprehensive Cancer Center: A Pilot Study to Assess Feasibility and Outcomes. Urologic Nursing. 2019;November-December 2019 / Volume 39 / Number 6:303-13.
13. Jensen BT, Laustsen S, Petersen AK, Borre M, Soendergaard I, Ernst-Jensen KM, et al. Preoperative risk factors related to bladder cancer rehabilitation: a registry study. European journal of clinical nutrition. 2013.
14. Gillis C, Buhler K, Bresee L, Carli F, Gramlich L, Culos-Reed N, et al. Effects of Nutritional Prehabilitation, With and Without Exercise, on Outcomes of Patients Who Undergo Colorectal Surgery: A Systematic Review and Meta-analysis. Gastroenterology. 2018;155(2):391-410.e4.
15. Jensen BT, Laustsen S, Jensen JB, Borre M, Petersen AK. Exercise-based pre-habilitation is feasible and effective in radical cystectomy pathways-secondary results from a randomized controlled trial. Support Care Cancer. 2016;24(8):3325-31.
16. Minnella EM, Awasthi R, Bousquet-Dion G, Ferreira V, Austin B, Audi C, et al. Multimodal Prehabilitation to Enhance Functional Capacity Following Radical Cystectomy: A Randomized Controlled Trial. Eur Urol Focus. 2019.
Dr. Bente Thoft Jensen, PhD, Chair, EAUN SIG Bladder Cancer, Aarhus (DK), b.thoft@eaun.org