Factors Influencing Quality of Life and Functional Outcomes in Patients With Bladder Cancer

Abstract

Here, we review the quality of life and functional outcomes of patients with bladder cancer after treatment and assess potential contributing factors. For current scoring systems, we highlighted the most commonly used specificity scores. In addition, we discuss the impact and bias on the quality of life of patients undergoing urinary diversion modalities, robotic surgery, perioperative rehabilitation, and bladder-preserving radiochemotherapy. Through this review, clinicians will gain better insights regarding the importance of improving patients' quality of life with the goal of restoring their patients’ normal function and participating in social activities.

Introduction

Bladder cancer (BC) is a common malignant tumor, often accompanied by high treatment costs and medical burden. ¹ BC can be divided into non-muscle-invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC). Currently, for patients with NMIBC, the main treatment methods are transurethral resection and intravesical therapy, while for patients with MIBC, radical cystectomy is the conventional treatment.

Complications and readmission rates are high following BC interventions, which can severely compromise patients’ functional outcomes. ² This reduction in quality of life manifests in many aspects, such as urination, digestion, and sexual function; furthermore, it damages personal image and social behavior, ultimately leading to varying degrees of psychological problems in patients.^3,4 The assessment of quality of life in patients with BC is diverse and complex. The heterogeneity of this disease makes it reasonable to combine cancer- and BC-specific scores. In addition, a detailed review of the potential impact of various interventions and population characteristics on the quality of life and functional outcomes is necessary to inform clinicians and patients.

Thus, in this article, we review the research tools used to assess the quality of life in patients with BC and impact of various interventions on quality of life.

Review

Assessment of Quality of Life

It is undeniable that the estimation of survival time is very important for patients with BC, but the quality of life represents whether the patient can retain the ability to live independently and hope of participating in social activities. Quality of life measures are important tools for assessing the clinical efficacy of cancer treatments. However, implementing quality of life measures in daily practice is challenging because quality of life measures are far from standardized. ⁵

Numerous measurement schemes, which are broadly divided into the BC-specific and BC-generic scales, have been developed over recent decades. However, many previously used or self-designed measurement protocols have poor reliability, not been validated across a wide range of regions and populations and are susceptible to bias. ⁵ Clinicians should understand each routine measurement protocol and familiarize themselves with its applicable scenarios and limitations.

Specific Scales for NMIBC

Two scales are available for patients with NMIBC. The European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Bladder Cancer Superficial 24 (EORTC QLQ-BLS24) or EORTC Quality of Life Questionnaire-Non-Muscle Invasive Bladder Cancer 24 (EORTC QLQ-NMIBC24), and Questionnaire of Quality of Life in patients with Non-Muscle Invasive Bladder Cancer (CAVICAVENMI).

In 1996, the EORTC produced the QLQ-BLS24 scale for NMIBC. The scale consists of 24 questions on urinary symptoms, chemotherapy tolerance, sexual and bowel functions, and other clinical aspects. EORTC recommends the use of this questionnaire as a supplement to the EORTC QLQ-C30 questionnaire to assess quality of life in NMIBC. ⁶ However, this questionnaire does not consider local and systemic adverse effects of chemotherapy drugs.

In 2014, researchers conducted the third stage of validation and reliability testing of QLQ-BLS24 scale for NMIBC, providing evidence of its reliability and validity. The data showed an evidence-driven adapted scale structure and psychometric data of the module for use in clinical trials of patients with intermediate- or high-risk BC. Accordingly, they revised the original scale and the final scale was renamed as EORTC QLQ-NMIBC24. ⁶ Although many studies have used this tool, data regarding its applicability in different countries and regions are lacking.^7,8

CAVICAVENMI was designed in 2016 by a Spanish research team. ⁹ Studies have shown that it has good validity and reliability. The CAVICAVENMI consists of 21 items, including disease state, self-evaluation, emotional state, work state, and sexual life. Its advantage is its simplicity as it is much shorter than the EORTC QLQ-NMIBC24 and EORTC QLQ-C30 questionnaires. This questionnaire also contained questions about the topical treatment of the mesentery and usage of mitomycin. Unfortunately, this questionnaire is currently available only in Spanish and, thus, has not been validated in other countries.

Specific Scales for MIBC

There exist three questionnaires that assess the quality of life of patients with MIBC. The first is the European Organisation for Research and Treatment of Cancer QLQ-BLM30 (EORTC QLQ-BLM30), ¹⁰ which is designed to measure the quality of life of patients with MIBC and is applicable to patients who underwent cystectomy and conservative treatment, but not for those received radiation therapy. Assessments include urinary symptoms, urethrostomy problems, catheter use, gastrointestinal symptoms, sexual function, and personal image. In the sexual module, questions cover issues that are specific to both men and women. The EORTC QLQ-BLM30 has been translated into 18 languages and is one of the most commonly used tools for assessing the quality of life in patients with MIBC. ¹¹

The second is the Functional Assessment of Cancer Therapy-bladder cystectomy (FACT-Bl-Cys)/FACT-Vanderbilt Cystectomy Index. The FACT-Bl-Cys was specifically designed for patients with MIBC in 2003. Similar to the EORTC QLQ-BLM30, it is a specific use case tool and is not designed for patients undergoing radiation therapy. ¹² Preliminary results show that the FACT-Bl-Cys is a reliable and valid questionnaire for assessing the quality of life of patients with BC. It assesses urinary, digestive, and sexual function, and body image. FACT-Bl-Cys was validated in a retrospective clinical study of 50 patients in 2003, and it was reported that it could objectively assess the quality of life after radical cystectomy and urinary diversion. ¹³ The third is the Ileal Orthotopic Neobladder-Pro Questionnaire (IONB-PRO). It was designed in 2014 to investigate the impact of radical cystectomy and ileal orthotopic neobladder. ¹⁴ The questionnaire includes questions on daily activities, emotional functioning, sleep disturbances, social functioning, and other issues. IONB-PRO is available in one long-form (23 items) and two short-form (12 items and 15 items) versions, and a study has shown its high validity, internal consistency, reliability, and good discrimination. ¹⁴ Furthermore, a study evaluated IONB-PRO and showed that it is a viable tool for assessing quality of life in patients with MIBC. ¹⁵

Ileal Conduit vs Orthotopic Neobladder

Radical cystectomy often results in lifestyle changes because the bladder is removed during this procedure, which increases care and cosmetic concerns. Patients who undergo the ileal conduit approach have their urinary function SCORES returned to baseline, but they do not experience urinary retention problems or incontinence. ¹⁶ In contrast, patients undergoing orthotopic neobladder surgery are able to urinate through the urinary tract. However, these patients are at a risk of reduced quality of life due to urinary retention or incontinence, in addition to complications associated with neobladder formation.

Since there is no difference in tumor prognosis between the ileal conduit and orthotopic neobladder, the choice of treatment regimen is mostly based on patient and physician preferences. There is considerable controversy in the academic community regarding the best methods of urinary diversion. A systematic review conducted by Sultan et al ¹⁷ showed that among patients who underwent radical cystectomy and urinary diversion, the use of the ileal conduit was associated with a reduced length of hospital stay and rates of major adverse events. However, they did not show clear advantages in terms of readmission rate, cardiovascular event rate, and narcotic drug requirement; therefore, they believe that the ileal conduit is the most effective and safest method of urinary diversion.

However, some studies have shown that an orthotopic neobladder approach is associated with better quality of life scores. Ghosh and Somani conducted a systematic review to explore the differences in quality of life between neobladders and other types of diversion surgeries. Results showed that 4–6 studies published after 2011 preferred neobladder diversion over other types of urinary diversion based on quality of life. ¹⁸ Singh et al ¹⁹ recently conducted a prospective study in which they concluded that the orthotopic neobladder approach was associated with improved quality of life. They showed that at 6, 12, and 18 months postoperatively, patients who underwent the orthotopic neobladder approach had significantly higher overall health status and quality of life than those who underwent the ileal conduit approach. Owing to research bias and lack of evidence, it is uncertain which surgery provides the best quality of life. We should note the biases in the studies of QOL of ileal conduit and neobladder. A major bias of QOL studies comparing neobladder and ileal conduit is that the neobladder patients tend to be quite younger and fitter. Further prospective studies with larger sample sizes are needed to validate these conclusions.

Open vs Robotic Surgery

Robots are important to perform minimally invasive surgeries. In developed countries, robotic surgery is an important method for performing radical cystectomy. ²⁰ Most robot-assisted radical cystectomies are performed in combination with open surgery. Among them, cystectomy and pelvic lymph node dissection are minimally invasive, and urinary diversion is an open surgery. ²¹ The totally intracorporeal orthotopic neobladder method has been shown to offer advantages such as good reproducibility, high surgical efficiency, and excellent perioperative outcomes.^21,22 Desai et al presented the experience of 132 patients who underwent complete intracorporeal robotic orthotopic ileal neobladder surgery after radical cystectomy. The results showed that the operative time, blood loss, length of hospital stay, and incidence of late complications improved with experience, and the 5-year overall, cancer-specific, and recurrence-free survival rates were 72%, 72%, and 71%, respectively. ²²

Many researchers have conducted studies to determine whether patients who underwent robot-assisted radical cystectomy had a better postoperative quality of life than those who underwent open surgery. In a small prospective clinical study, Poch et al assessed the quality of life of patients after robot-assisted radical cystectomy. They concluded that urine output and bowel function returned to baseline at 1–2 months and 2–4 months, respectively. Quality of life scores for sexual function declined the most but returned to normal 16–24 months after surgery. ²³ A meta-analysis of five randomized-controlled trials by Sathianathen et al ²⁴ showed no differences in disease progression, major complications, or quality of life between robot-assisted and open radical cystectomy. However, robot-assisted radical cystectomy has shown reduced risk of perioperative blood transfusion and shorter hospital stay. Notably, open radical cystectomy appears to have a lower rate of local recurrence.

It must be noted that all the abovementioned meta-analyses used the extracorporeal urinary diversion method. Recently, the intracorporeal urinary diversion method has become popular because it does not require additional incisions to create a new bladder. A study by the International Robotic Cystectomy Consortium showed that the use of intracorporeal urinary diversion increased from 0% in 2005 to 95% in 2018. ²⁵ However, the bias in that survey should be acknowledged. However, patients with intracorporeal urinary diversion appeared to have more overall complications and readmission rates, but high-grade complications did not show significant differences. Another study by this consortium noted that patients with intracorporeal urinary diversion showed shorter operative times, less blood loss, and fewer blood transfusions. However, this subset of patients experienced more advanced complications. ²⁶ Although intracorporeal urinary diversion was associated with higher-grade complications than extracorporeal urinary diversion, the complications decreased over time.

Recently, a well-designed, open-label, randomized, phase 3, non-inferiority trial of the efficacy of robotic surgery was published. ²⁷ In this trial, 350 participants were randomly grouped into the robotic-assisted radical cystectomy or open radical cystectomy group between July 1, 2011 and November 18, 2014. The 2-year progression-free survival rates were 72.3% and 71.6% in the robotic cystectomy and open cystectomy groups, respectively, indicating the non-inferiority of robotic cystectomy. In addition, the authors assessed the patients’ quality of life using the FACT-Bl-Cys questionnaire at baseline and 3 and 6 months postoperatively. The authors observed that there was no significant difference in FACT-Bl-Cys scores between the two groups at any time point and that the mean total FACT-Bl-Cys score at 6 months postoperatively significantly improved in both groups. A possible reason for this is that all urinary diversions are extracorporeal, which may obscure the potential benefits of robot-assisted radical cystectomies. ²⁸

Satkunasivam et al ²⁹ evaluated bladder cancer-specific and general health-related quality of life outcomes between intracorporeal orthotopic neobladder and extracorporeal urinary diversion. Quality of life scores for urinary function and urinary bother were similar between the groups, and the surgical type was not associated with the score on multivariable analysis. Rates of 24 hours pad use were similar between the intracorporeal and extracorporeal orthotopic neobladder groups, as reflected by the total pad usage (P = .1).

Sex Differences

Although the quality of life is a particularly important issue for women, especially those who have social needs or are sexually active, most studies on quality of life after BC surgery have excluded women.

However, a few of them have addressed this issue. Smith et al ³⁰ conducted a systematic review assessing women's functional outcomes in three domains: voiding function, sexual function, and quality of life. The authors reported that about 20% of patients had daytime incontinence, 20% had nocturnal incontinence, and 10%–20% had hyper-continence. Additionally, they reported that sexual function appears to improve in patients undergoing genital-sparing radical cystectomy. Furthermore, the differences in the quality of life between patients undergoing different urinary diversion procedures were minimal. The authors also compared patients with the general population and found significant differences in emotional problems, role functioning, fatigue, and appetite. However, all studies included in this systematic review were at a high risk of bias and varied widely with respect to sample size, inclusion criteria, and duration of follow-up; therefore, these findings should be treated with caution.

Several studies have compared the differences in the quality of life between male and female patients. In a cross-sectional study, female patients appeared to have better sexual function than male patients. ³¹ Female sexual function may be affected by body perception and personal image, whereas male patients may experience issues such as erection and ejaculation function. The authors observed that than men, women who underwent the ileal conduit approach had lower scores on cognitive function and future outlook. However, men who underwent the ileal conduit method had lower sexual function scores than women did. Than male patients, female patients bear a greater psychological and social burden in terms of cognitive function and future outlook. In addition, the authors compared the impact of orthotopic ileal neobladders and ileal conduits on quality of life. The data showed non-statistically significant differences between the two groups in terms of median follow-up time, pathological stage, tumor grade, adjuvant chemotherapy or radiotherapy, and quality of life.

The recovery of sexual function is also one of the main concerns for sexually active women. During radical cystectomy, damage to the neurovascular bundles located in the lateral wall of the vagina may lead to impaired sexual function. ³² Moreover, because the anterior vaginal wall is often removed along with the bladder, vaginal shortening or narrowing may occur after radical cystectomy. Bhatt et al ³³ conducted a cohort study to explore the effects of neurovascular preservation after radical cystectomy and neobladder construction. The authors analyzed six domains of sexual function (desire, arousal, lubrication, orgasm, satisfaction, and pain) using the Female Sexual Function Index questionnaire. In the nerve-sparing group, the scores at baseline and 12 months after surgery showed a small decrease, whereas in the non-nerve-sparing group, there was a significant decrease in baseline and postoperative scores. In the non-nerve-sparing group, 6 of the 7 patients eventually stopped having sexual intercourse. Therefore, the authors concluded that female sexual function was preserved in the patients who received neurovascular protection.

Zippe et al ³⁴ investigated baseline and follow-up data of 27 sexually active female patients who underwent radical cystectomy from 1997 to 2002 using a 10-item version of the self-administered Index of Female Sexual Function questionnaire to assess sexual dysfunction. They showed that the most common symptoms reported by patients included decreased ability or inability to achieve orgasm (45%), decreased lubrication (41%), decreased libido (37%), and dyspareunia (22%). The authors suggested that sexual dysfunction was a common problem in women after radical cystectomy. Surgical procedures such as urethral and vaginal sparing, neurovascular sparing, and tubular vaginal reconstruction may improve female sexual function.

Pre and Postoperative Rehabilitation

Frailty is a complex, multidimensional state of diminished physiological reserves that leads to a decrease in a patient's resilience and adaptability, and ultimately leads to an increase in physical vulnerability. In one study, 21.8% of patients with urinary tract cancer aged >70 years were found to be frail. ³⁵ Some researchers believe that postoperative physical and dietary interventions can effectively eliminate frailty in high-risk groups. ³⁶

There is a growing desire to improve health through systematic rehabilitation interventions and thereby improve the quality of life and functional outcomes in patients with BC. Jensen et al ⁸ conducted a study to assess whether a standardized postoperative physical activity program affects quality of life and patient satisfaction in patients undergoing radical cystectomy. Compared with the control group, the intervention group had significantly improved quality of life scores in areas such as dyspnea, constipation, and abdominal bloating. However, the rehabilitation interventions did not affect hospital patient satisfaction. Another randomized-controlled trial investigated the effect of postoperative physical activity in patients with BC who underwent radical cystectomy. ³⁷ The intervention group included twice-weekly exercise training and daily walks, using the SF-36 to assess functional ability, balance, lower body strength, and health-related quality of life.

Karl et al ³⁸ investigated the impact of early recovery after surgery in patients who underwent radical cystectomy. Quality of life measured using the EORTC QLQ-30 questionnaire did not change significantly between postoperative days 3 and 7 and at discharge from the hospital in the control group, whereas a significant improvement was observed in the early recovery after surgery group. The authors concluded that early recovery after surgery in patients who underwent radical cystectomy has significant advantages over conservative management in terms of postoperative morbidity, quality of life, and analgesic use. Sapre and Murphy believe that although there is insufficient evidence for the exact advantage of early recovery after surgery, the available evidence suggests that early recovery after surgery may accelerate the recovery of patients who underwent radical cystectomy; therefore, clinicians must change the traditional perioperative management to facilitate better recovery. A multidisciplinary approach involving surgeons, anesthesiologists, nurses, nutritionists, and allied health professionals is the key to optimize patient recovery. ³⁹

Bladder-Preserving Radiochemotherapy

Few studies have compared the use of radiotherapy as a bladder-sparing strategy performed with radical cystectomy. Perlis et al ⁴⁰ conducted a systematic review of the quality of life of patients with BC treated with radiotherapy. They found that the majority of patients who received radiotherapy as a bladder-sparing strategy had good or satisfactory bladder, bowel, and sexual function. The patients had better quality of life or recovered better than patients who underwent cystectomy alone. They reported that the most serious complication was the urgency to defecate, and the most common adverse events were diarrhea/loose stools and fecal incontinence. Bowel discomfort is the most frequently reported quality of life problem in patients with BC after radiation therapy. In addition, unpleasant symptoms include frequent urination, sexual disturbance, fatigue, and discomfort.

Botteman et al ⁴¹ suggested that bladder-sparing strategies have better short-term clinical outcomes in terms of physical, psychological, and sexual function.

However, other studies have reported contradictory conclusions. Fokdal et al found that after radical radiotherapy, most patients had good bladder function, whereas 14% reported moderate-to-severe bladder dysfunction. Radiotherapy is inevitably associated with long-term intestinal side effects owing to the presence of the bowel in the radiotherapy area. Radiotherapy can also cause sexual dysfunction. ⁴²

Conclusion

In addition to oncological outcomes, treatment burden and quality of life are major concerns for patients and clinicians, and the focus of BC treatment is shifting from mere survival to ensuring good quality of life. Overall, researchers should focus on better understanding the quality of life of patients with BC to appropriately address this growing medical need. Several valid quality of life questionnaires have been developed over the past few decades; however, no procedures have been established for collecting quality of life survey results. In addition, longitudinal prospective large-scale cohort studies on the quality of life of patients with BC are still lacking, and this gap needs to be filled.