By Dr. Alejandro R. Rodríguez (Rochester, US), Secretary General of the Confederación Americana de Urología (CAU)
This article reflects the highlights of the lecture Dr. Alejandro R. Rodríguez will be giving during “Plenary Session 03 – Advanced bladder cancer in 2021: Going forward?” at EAU21 Virtual. This session is taking place in Virtual Room 1 on Saturday 10 July, from 11.00 – 12.30 CEST.
Bladder cancer is the 10th most diagnosed cancer worldwide, with approximately 573,000 new cases and 213,000 deaths. It is more common in men than in women, with a respective incidence and mortality rate of 9.5 and 3.3 per 100,000 men globally, approximately 4 times more than among women. 
In 2021, there will be an estimated 83,730 new cases and 17,200 new deaths due to bladder cancer in the USA. It is the 4th most common cause of cancer in men just behind prostate, lung/bronchus, and colon/ rectum cancer. 
Given that the median age at diagnosis is 73 years, medical comorbidities are a frequent consideration in patient management. The clinical spectrum of bladder cancer can be divided into 3 categories that differ in prognosis, management and therapeutic aims. The first category consists of non-muscle-invasive diseases, for which treatment is directed at reducing recurrences and preventing progression to a more advance stage. The second group encompasses muscle-invasive diseases. As for patients in this group, it should be determined whether the bladder should be removed or if it can be preserved without compromising survival and whether the primary lesion can be managed independently or whether the patient is at high risk for distant spread requiring systemic approaches to improve the likelihood of cure. The critical concern for the third group, which consists of metastatic lesions, is how to prolong and maintain quality of life.
Bladder cancer staging
The goal of transurethral resection of bladder tumour (TURBT) is to correctly identify the clinical stage and grade of disease while completely resecting all visible tumour. Therefore, an adequate sample that includes bladder muscle should be obtained in the resection specimen. A small fragment of tumour with few muscle fibres is inadequate for assessing the depth of invasion and guiding treatment recommendations.
The most used staging system is the tumour, node and metastasis (TNM) staging system by the American Joint Committee on Cancer (AJCC).  Approximately 75% of newly detected cases are non-muscle-invasive disease (NMIBC) and 25% are muscle invasive (MIBC). Clinical investigation of the specimen obtained by TURBT is an important step in the diagnosis and subsequent management of bladder cancer. The modifier “c” before the “stage” refers to clinical staging based on bimanual exam under anaesthesia, TURBT and imaging studies. A modifier “p” would refer to pathologic staging based on cystectomy and lymph node dissection.
Muscle-invasive bladder cancer (MIBC)
MIBC (T2) is defined as a malignant extension into the detrusor muscle while perivesical tissue involvement defines a T3 disease. Extravesical invasion into the surrounding organs (the prostatic stroma, seminal vesicles, uterus, vagina, pelvic wall, abdominal wall) delineates T4 disease. The depth of invasion is the most important determinant of prognosis and treatment for localised bladder cancer.
Several workup procedures are recommended to accurately determine the clinical stage of MIBC. Laboratory studies, such as a complete blood cell count and chemistry profile, including alkaline phosphatase, must be performed, and the patient should be assessed for the presence of regional or distant metastases. This evaluation should include chest imaging (CT, x-ray, or FDG-PET/CT) and evaluation for suspected bone metastasis in patients with symptoms or clinical suspicion of bone metastasis (elevated alkaline phosphatase, focal bone pain). Chest imaging with CT is preferred over chest imaging with X-ray. This is based on studies that showed a better sensitivity of CT for detection of metastatic disease. Bone imaging may include a bone scan, MRI, or FDG-PET/CT. Imaging studies help assess the extent of the tumour spread to the lymph nodes or the distant and regional extent of the disease. Unfortunately, CT-scans, ultrasounds and MRIs cannot accurately predict the true depth of invasion (see figure 1 and 2).
Figure 1: A bladder tumour of 2 cm. Seemed non-invasive; however, it was a T2 high-grade
Figure 2: A bladder tumour of 8 cm. Seemed muscle-invasive; however, it was a Ta low-grade
Role of TUR in MIBC
Although the overwhelming majority of muscleinvasive tumours are high-grade urothelial cancer, TUR for MIBC will not only give you the clinical stage and grade of the primary tumour, but it will also play an important role in identifying the type of histology (especially variant histology) that could change your management approaches to MIBC. We need to remember that approximately 10% of the bladder tumours are non-urothelial (non-transitional) carcinoma. These pathologic entities include mixed-histology, pure squamous, adenocarcinoma, small-cell tumours, urachal carcinoma, or primary bladder sarcoma. The presence of histologic variants in urothelial carcinoma should be documented as data suggest that the subtype may reflect the risk of disease progression and a different genetic etiology and may subsequently determine whether a more aggressive treatment approach should be considered. In some cases with a mixed histology, systemic treatment may only target cells of urothelial origin and the non-urothelial component can remain. The 4th edition of the World Health Organization (WHO) classification of tumours has classified these histologic subtypes into the following: nested, including large nested; microcystic; micropapillary; lymphoepithelioma-like, plasmacytoid/signet ring cell/diffuse; sarcomatoid; giant cell; poorly differentiated; lipid-rich; clear cell; infiltrating urothelial carcinoma with divergent differentiation. 
For MIBC of urothelial origin, further treatment following initial TURBT is often required, although selected patients may be treated with TURBT alone. TURBT alone may be an option for patients with stage-II disease who are not candidates for cystectomy. TURBT alone may be curative in selected cases that include solitary lesions less than 2 cm in size that have minimally invaded the muscle. These cases should also have no associated in situ component, palpable mass or associated hydronephrosis. If primary treatment consists of TURBT alone, patients should undergo an aggressive re-resection of the site within 4 weeks of the primary procedure to ensure that no residual disease is present. If repeat TURBT is negative for residual tumour, the patient can be managed conservatively with repeat endoscopic evaluations and cytologies every 3 months until a relapse is documented. The stage of the lesion documented at relapse would determine further management decisions. [5-7]
TUR for MIBC is also important in bladder preservation options. All bladder-sparing approaches are based on the principle that not all cases require an immediate cystectomy, and the decision to remove the bladder can be deferred until the response to organ-sparing therapy is assessed. Bladderpreserving approaches are reasonable alternatives to cystectomy for patients who are medically unfit for surgery and those seeking an alternative to radical cystectomy.
The decision to use a bladder-preserving approach should be partially based on the location of the lesion, depth of the invasion, size of the tumour, status of the “uninvolved” urothelium, and status of the patient (bladder capacity, bladder function, comorbidities). Bladder preservation as an alternative to cystectomy is generally reserved for patients with smaller solitary tumours, negative nodes, no extensive or multifocal CIS, no tumour-related hydronephrosis, and a good pre-treatment bladder function. Maximal TUR with concurrent chemoradiotherapy should be given as a primary treatment to these patients.
This modality is endorsed by multiple international organisations that have developed evidence-based consensus guidelines and recommendations, including the International Consultation on Urologic Disease-European Association of Urology (ICUD-EAU), UK National Institute for Health and Care Excellence (NICE) and the AUA/ASCO/ASTRO/SUO. There is an apparent underutilisation of aggressive bladderpreserving therapies for non-cystectomy candidates, especially the elderly and racial minorities. Between 23% and 50% of the patients with muscle-invasive bladder cancer who are 65 years and older of age receive no treatment or non-aggressive therapy, despite prospective, phase-II data showing that bladder preservation with trimodality therapy has positive outcomes and an acceptable toxicity profile for patients >=65 years of age, with a 2–year OS of 94.4% and 2-year DFS of 72.6%. 
The role of TUR in MIBC is to obtain tissue for the histopathological diagnosis, grading and clinical staging of the tumour. TUR for MIBC should also achieve macroscopic clearance where possible. In a select few patients, TUR alone for MIBC may be a reasonable alternative to other more invasive options. Maximal TUR with concurrent chemoradiotherapy may be given as a real primary treatment to patients that look for bladder preservation as an alternative to radical cystectomy.
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