Bladder Cancer: Management and Outlook

Bladder carcinoma (BC) is the most common neoplasm of the urinary system. It is the 10th most common cancer worldwide; the 6th most common cancer in men and the 17th most common cancer in women.

573,278 new cases of bladder cancer were diagnosed globally in 2020, and over 212,536 deaths due to BC were recorded.

We spoke with Theresa Lowry Lehnen, Clinical Nurse Practitioner and Associate Lecturer South East Technological University to find out more about the diagnosis, management and outlook for this condition.

The condition occurs four times more often in men than women. The age-standardised incidence rate per 100, 000 person-years is 9.5 for men and 2.4 for women worldwide, and in the EU, 20 for men and 4.6 for women.

Theresa told us, “Approximately 490 people in Ireland are diagnosed with bladder cancer annually. The incidence increases with age. Approximately 70 per cent of patients diagnosed with bladder cancer in Ireland are over 65 years of age, and up to 15% are diagnosed with metastatic disease at initial presentation.”

Urothelial carcinoma (UC) also known as transitional cell carcinoma (TCC) is the most common histologic type of bladder cancer, accounting for approximately 90% of cases. She adds, “The incidence of bladder cancer is twice as high in developing countries compared to developed countries. Most bladder cancers in developing countries are squamous cell carcinoma, and correlate with endemic schistosomiasis.”

There are three types of bladder cancer:

1. Transitional cell carcinoma (TCC) or urothelial carcinoma (UC) which begins in cells in the innermost tissue layer of the bladder. These cells can stretch when the bladder is full and shrink when it is emptied. Most bladder cancers begin in the transitional cells. Transitional cell carcinoma can be low-grade or high-grade:

• Low-grade transitional cell carcinoma often recurs after treatment, but rarely spreads into the muscle layer of the bladder or to other parts of the body.

• High-grade transitional cell carcinoma often recurs after treatment and often spreads into the muscle layer of the bladder, to other parts of the body, and to lymph nodes. Almost all deaths from bladder cancer are due to high-grade disease.

2. Squamous cell carcinoma begins in squamous cells, which are thin, flat cells lining the inside of the bladder. Cancer may form after long-term infection or irritation.

3. Adenocarcinoma: Cancer that begins in glandular cells that are found in the lining of the bladder. This is a very rare type of bladder cancer. Cancer in the lining of the bladder is called non-muscle-invasive bladder cancer (superficial). Cancer that has spread through the lining of the bladder, and which invades the muscle wall of the bladder or has spread to nearby organs and lymph nodes is called muscle invasive bladder cancer.

Risk Factors

There are multiple risk factors for bladder cancer, including increasing age, family history, genetic mutations, smoking, schistosomiasis infection, and occupational exposure to certain chemicals. The risk in smokers depends on smoking duration and intensity, and is 2 to 6 times higher than in non-smokers.

Theresa says, “Smoking is the most important risk factor for bladder cancer and thought to cause about half of all bladder cancers. Occupational exposure to paint, rubber, petroleum products, and dyes, and chemicals such as arylamine, aniline, phenacetin and arsenic are associated with bladder cancer, and exposure to the chemotherapy drug cyclophosphamide has been associated with an increased risk.

“Chronic urinary tract infections and infection with the parasite S. haematobium is also associated with an increased risk of bladder cancer, often squamous cell carcinomas. In developing countries, schistosomiasis infection is an important cause of BC. Schistosoma haematobium ova embed in the bladder wall leading to irritation, chronic inflammation, squamous metaplasia, and dysplasia, with further progression leading to squamous cell carcinoma of the urinary bladder.

“Mutations in the p53 tumour suppressor gene, as well as abnormalities in chromosome 9, are common in invasive bladder cancer. Inherited mutations of two other genes, glutathione S-transferase (GSTM1) and NAT2 (n-acetyltransferase), also increase risk for bladder cancer.”

Clinical Features

Bladder cancer typically presents with gross or microscopic haematuria. Less commonly, patients may complain of urinary frequency, nocturia, and dysuria; symptoms that are more common in patients with carcinoma in situ.

Other symptoms may include fatigue, weight loss, and a pelvic mass, according to Theresa, who adds that patients with upper urinary tract urothelial carcinomas may present with pain resulting from obstruction by the tumour.

Diagnosis

“There are no screening tests for the early detection of BC,” she notes. “Despite the search for urinary biomarkers for the early and non-invasive detection of bladder cancer, no biomarkers are used at present in daily clinical practice. Diagnostic modalities used in diagnosing BC include Imaging (ultrasound, intravenous urography (IVU), computed tomography (CT), and magnetic resonance imaging (MRI)); cystoscopy, and biopsy.

“Cystoscopy is an effective but invasive tool to detect bladder cancer tumours. It is considered the gold standard and most useful diagnostic test. Direct visualisation of the bladder is necessary in all cases of haematuria, where there is a concern for bladder cancer, and no imaging modality is currently sensitive enough to replace cystoscopy.

“The main role of imaging in the assessment of haematuria is to evaluate the kidneys and ureters. Ultrasound or CT may be used, and guidelines differ in their recommendation regarding imagery. Ultrasound of the kidneys will identify most renal tumours; however, it can miss a small percentage of upper tract urothelial cancers which can be detected with CT scanning. Urine cytology remains an important diagnostic tool, and is a non-invasive diagnostic method where voided or instrumented urine is examined for exfoliated cancer cells. The overall sensitivity ranges from 28 to 100%, with a median of 44%. It has a high sensitivity for high-grade tumours, but low sensitivity for low-grade tumours, ranging only from 4% to 31%.

“Cytology is useful, particularly as an adjunct to cystoscopy, when a high-grade malignancy is present. A positive cytology indicates a urothelial tumour anywhere in the urinary tract, however, negative cytology does not exclude the presence of a tumour. In some cases, a bone scan or PET scan may be recommended, but are not normally required, especially with non-muscle invasive bladder cancer.”

Grading and Staging

Grading describes how quickly the cancer may grow and spread.

• Low-grade bladder cancer: The cancer cells look only slightly abnormal, much like normal bladder cells. The cancer is usually slow-growing and less likely to spread than high grade bladder cancer.

• High-grade bladder cancer: The cancer cells look fairly or very abnormal and are more likely to grow quickly. Carcinoma in situ (CIS) is always classed as high grade.

Staging using TNM scores, describes how deeply the cancer has grown into the bladder and if it has spread to other parts of the body. TNM stage is the most important prognostic factor of urinary bladder carcinoma.

• Tumour (T): How deeply the tumour has grown into the bladder.

• Node (N): Is there cancer in the lymph nodes?

• Metastasis (M): Has the cancer has spread to other parts of the body?

The most common bladder cancer – non-muscle-invasive bladder cancer is staged as follows:

• Carcinoma in situ (CIS): This appears as flat, red areas in the bladder. This type of bladder cancer is more likely to come back after treatment, often as another non-invasive cancer in the bladder. CIS is always classed as high grade. It can grow more quickly and can become invasive, requiring different treatment to other non-muscle-invasive bladder cancers.

• Ta: The tumour is found as a papillary cancer growing only in the innermost lining of the bladder.

• T1: The tumour has started to grow into the connective tissue just below the bladder lining.

The rarer muscle-invasive bladder cancer is staged as follows:

• T2: The tumour has grown into the muscle layer in the bladder. It is divided into T2a and T2b.

• T2a: the cancer has grown into the superficial muscle

• T2b: the cancer has grown into the deeper muscle

• T3: The tumour has spread through the muscle layer to the outer fat layer around the bladder.

It is divided into T3a and T3b.

• T3a: microscopic invasion

• T3b: macroscopic invasion

Advanced / metastatic bladder cancer

• T4: The cancer has spread outside the bladder to other organs.

It is divided into T4a and T4b.

• T4a: With locally advanced disease, the cancer may have spread into the pelvic wall, the prostate in men, or the uterus or vagina in women.

• T4b: In distant metastases, the cancer has spread beyond the surrounding areas, to other parts of the body such as the liver, bones or lungs.

Nodes (N)

• N0: No cancer is found in any of the lymph nodes.

• N1: Cancer is found in one lymph node and is smaller than 2 cm.

• N2: Cancer is found in one lymph node and is bigger than 2 cm but less than 5 cm or the cancer has spread to more than one lymph node, but is smaller than 5 cm.

• N3: Cancer is found in at least one lymph node and is 5 cm in size.

Metastasis (M)

• M0: Cancer has not spread to other parts of the body.

• M1: Cancer has spread to other parts of the body. This is known as secondary, metastatic or advanced bladder cancer. M1 can be divided into M1a and M1b.

• M1a: Cancer has spread to the lymph nodes outside the pelvis.

• M1b: Cancer has spread to other parts of the body such as the bones, lungs and liver.

Treatment and Management

Bladder cancer is a prevalent disease with substantial morbidity and mortality which requires interprofessional medical and surgical management, she says. “Treatment is based on the pathological findings of the biopsy, with attention to histology, grade and depth of invasion.”

The most common types of treatments used for bladder cancer are surgery, chemotherapy, immunotherapy, targeted therapy and radiation therapy.

NMIBC- non-muscle-invasive bladder cancer

“NMIBC is the most common diagnosed bladder cancer and refers to bladder cancers confined to the mucosa (pTa) or lamina propria (Pt1), without invasion of the bladder wall muscle. CIS, a high-grade fat tumour confined to the mucosal layer, is also included in this group. pTa and pT1 appear as papillary type lesions and the number and size of tumours are important predictors for the risks of progression and reoccurrence. CIS tumours can appear as changes on the bladder mucosa and often present with lower urinary tract symptoms rather than haematuria.

“Management of NMIBC includes transurethral resection of bladder tumour (TURBT), a diagnostic and therapeutic procedure that allows the collection of samples to determine the grade and stage of bladder cancer. The samples are sent for histological assessment. NMBIC has the potential to reoccur or progress to muscle invasive bladder cancer (MIBC).

“The European Organisation for Research and Treatment of Cancer (EORTC) developed a scoring model for predicting recurrence and progression. The scoring system is based on assigning points for- number of factors; tumour diameter; prior recurrence rate; category; concurrent CIS; and World Health Organisation (WHO) 1973 tumour grade.”

Theresa adds that surveillance after treatment such as trans urethral resection of bladder tumour (TURBT) uses different modalities including regular cystoscope evaluation, CT scan and cytology. Intravesical treatments including chemotherapy agents mitomycin, epirubicin and BCG are important in the reduction of recurrence and progression rates of NMBIC.

Management of MIBC- muscle invasive bladder cancer

“While most patients presenting with bladder cancer have NMIBC, up to 25 per cent have muscle invasive bladder cancer (MIBC), where cancer cells are detected in the muscularis mucosa at the time of TURBT. Tumours that extend to the muscle layer are staged T2, to the perivesical fat T3, and those that invade other organs or the pelvic side wall, T4,” she says.

“Muscle invasive bladder cancer cannot be cured with endoscopic treatments alone and requires radical therapy. Even with radical treatments the five-year survival rate is approximately 50%.

Treatment options for MIBC include radical cystectomy, neoadjuvant chemotherapy (NAC), urinary reservoir reconstruction, trimodal therapy, radiotherapy, and endoscopic management. In radical cystectomy the prostate gland and seminal vesicles are also removed in men and the urethra is removed if a tumour is detected on urethral biopsy. In women the uterus, urethra and adjacent vaginal tissues are removed, however, the ovaries can usually be left in situ. Regional lymph nodes are also removed in both men and women.

“The addition of neoadjuvant chemotherapy (NAC) has been shown to account for a 5 per cent improvement in overall survival with radical cystectomy. NAC should be commenced as soon as possible and followed by surgery usually within six weeks. Ileal conduit is the most common method of urinary reservoir reconstruction in Ireland and the UK.

“The Studer neobladder is another technique, but is contraindicated when a tumour has spread to the urethra. Trimodal therapy utilises TURBT, radiotherapy and chemotherapy. In carefully selected patients, results from trimodal therapy can match those of radical cystectomy. External beam radiotherapy should not be offered as a primary therapy and only be considered in patients unfit for cystectomy.

“Endoscopic resection and diathermy for patients with unresectable disease can improve the quality, but not quantity-of-life. Standard first-line treatment for metastatic urothelial cancer is gemcitabine/cisplatin (GC) or MVAC (methotrexate, vinblastine, adriamycin and cisplatin). Approximately 50% of patients are unfit for cisplatin-containing chemotherapy due to poor hearing, impaired renal function or comorbidity.”

Prognosis and complications

Bladder cancer is a prevalent disease with substantial morbidity and mortality that requires multidisciplinary medical and surgical management. NMIBC can be completely managed endoscopically with the occasional use of intravesical treatments. Strict surveillance is necessary to help prevent recurrence or progression.

Theresa adds, “MIBC is more progressive and treated with radical cystectomy/radical cystoprostatectomy and ileal conduit formation following NAC. Long-term follow-up is required to monitor recurrence and functional deterioration. The prognosis of UC depends on multiple factors. “The TNM stage is the most important prognostic factor of urinary bladder carcinoma. The five-year overall survival for pT1 is 75%, pT2 50%, and pT3 20%.”

Up to 45% of patients will develop complications following radical cystectomy and ileal conduit formation. Main complications include vitamin B12 deficiency, metabolic acidosis, and deterioration of renal function, urinary tract infections, and anastomotic complications. The general 5-year survival rate for people with bladder cancer is 77%. However, survival rates depend on many factors, including the type and stage of bladder cancer that is diagnosed. Advanced and metastatic bladder cancer has a poor prognosis and median survival even with cisplatin-based chemotherapy is approximately 14 months.

Theresa concludes, “Ongoing clinical trials are increasingly showing an overall survival benefit with immunotherapy and targeted treatment for bladder cancer. Researchers are studying new combinations of chemotherapies and other medications to see if they are safe and more effective than other treatments. Clinical trials are underway to find a better way of reducing symptoms and side effects of current treatments to improve comfort and quality of life for patients.”

An interview with Theresa Lowry Lehnen, RGN, RNP, PhD, Clinical Nurse Specialist and Associate Lecturer with South East Technological University

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