Nonmuscle invasive bladder cancer

Approximately 70% of bladder tumors are non-muscle invasive at diagnosis.

These patients have a generally favorable prognosis but they can often recur and progress.
Recurrence and progression of disease is stage and grade dependent and are important markers for patient management.
About 40-80% of those treated for NMIBC will experience a recurrence within a year.
Recurrence of NMIBC is attributed to four mechanisms: incomplete resection, tumors cell re-implantation, microscopic tumor growth, and new tumor formation.
Initial treatment includes transurethral resection of all visible bladder tumor, followed by observation or intravesical therapy depending on the stage, grade, and risk factors.
Low-grade pTa tumors have an estimated recurrence rate and progression of 55% and 6%, respectively, compared with the rate of 45% and 17% for high-grade pT1 tumors.
BCG is the cornerstone of intravesical therapy.
BCG vaccine is the recommended intravesical therapy for high-risk NMIBC, along with frequent surveillance through cystoscopy.
Transurethral resection is diagnostic and therapeutic for NMIBC.
For patients unresponsive to BCG or there is a high risk of local and distant progression the standard of care is radical cystectomy.
Alternative intravesical therapies include gemcitabine, docetaxel, epirubicin  and Mitomycin.
In the above patients who are unfit for cystectomy salvage intravesical therapy is indicated.
Endoscopic resection can optimize treatment response and can achieve pT0 in upwards of 15% of patients with clinical T2 disease.
TURBT,complete endoscopic resection of all papillary tumor and appropriate sampling of the muscularis propria in high risk patients should be done.
For patients with high-grade T1 tumors, the rates of residual disease and pathological upstaging approximately 50% and 10%, respectively.
Guidelines call for repeat transurethral resection of all high-grade T1 lesions.
TURBT produces unoriented, piecemeal specimens making margin evaluation impossible.
Presently enblock resection of endophytic bladder tumors has been recommended.
Bipolar/monopolar resection and YAG laser techniques achieve similar outcomes to TURBT.
TURBT is performed with white light, which. Issues approximately 25% of TaT1  papillary tumors in 27% of carcinoma in situ lesions.
Photo dynamic diagnosis using blue light to fluorescently visualize a photoactive porphyrin either 5-aminolevulinic acid or hexaainoevuinate hydrochloride instilled  intravesically before TURBT.
Metaanalyses show blue light cystoscopy reduced rates of recurrence but does not affect progression or mortality compared with white light cystoscopy.
Blue light cystoscopy is associated with false positives from inflammation, intravesical therapy, and recent instrumentation, reducing its specificity for lesion detection compared with white light cystoscopy.
Primary Tis a high-grade lesion of the urothelium and standard therapy is resection followed by intravesical therapy with BCG.
For cTa high-grade, cT1 andTis follow up is recommended with urinary cytology and cystoscopy at 3-6 month intervals  for the first two years and longer intervals thereafter.
BCG is preferred over intravesical chemotherapy on Tis, based on randomized trials with a higher complete response rate and the longer duration of remission.
In patients with NMIBC who are unresponsive to BCG, and who are not cystectomy candidates Pembrolizumab is approved therapy.
Maintenance Intravesical therapy maybe considered after induction with chemotherapy or BCG, but it’s roll is controversial.
The role of maintenance BCG in patients with intermediate to high risk non-muscle invasive bladder cancer is more well established.
The strongest date is supports every three week BCG maintenance regimen, that has demonstrated reduce disease progression and metastasis.
Pembrolizumab has been evaluated in the treatment of BCG unresponsive, non-muscle invasive bladder cancer with carcinoma in situ and has reported response rates of approximately 40% with median duration of responses of 16.2 months with 46% of complete responses maintained for at least a year.
TURBT is the standard treatment for Ta, low-grade tumors.
TURBT alone can eradicate these tumors but it is recommended to administer one dose  of intravesical chemotherapy within 24 hours of resection to reduce recurrence risks.
Tumor stage cTa that are high grade papillary tumors have a relatively high risk of recurrence and progression towards more invasiveness.
If no muscle is present on the specimen the patient should have repeat resection to rule out muscle involvement.
Patients with high-grade cTA tumors after TURBT should be treated with intravesical BCG to prevent recurrences.
Most cT1 lesions are high grade and are potentially dangerous with a higher risk of recurrence and progression.
These lesions are treated with complete endoscopic resection and repeat TURBT is strongly advised within 2 to 6 weeks, followed by adjuvant intravesical therapy.
if residual cT1 disease is found at repeat TURBT BCG treatment or cystectomy should be entertained.
High risk T1  disease includes patients with multifocal lesions,  tumors associated with CIS or lymphovascular invasion and variant histology or lesions that recur if the BCG an early cystectomy may be preferred in these patients.
For a patient with low risk, non-muscular invasive bladder cancer, if the initial follow up surveillance cystoscopy is negative within four months of TURBT, the next cystoscopy is recommended 6 to 9 months later and then yearly for up to five years.
Follow up cystoscopy after five years should be performed only on the basis of clinical indication.
Patients under observation after initial TURBT showing a recurrence using cystoscopy should only go another TURBT and then adjuvant intravesical therapy or cystectomy based on the stage and grade of the recurrent lesion.
Experimentally neoadjuvant intravesical mitomycin administered one day and four hours prior to TURBT did reduce recurrence rate.
Nadofaragene firadenovecvncg gene therapy, a non-replicating adenoviral vectored based gene therapy has been approved for adults whose non-muscle invasive bladder cancer did not respond to immunotherapy with BCG.
Intravesical gemcitabine has demonstrated activity for recurrent non-muscle invasive bladder cancer after BCG.
Pembrolizumab is a an option for patients with BCG unresponsive and high-risk disease.
Patients with residual disease after TURBT and BCG should proceed to cystectomy.

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