1.  DIAGNOSIS AND PATHOLOGY/MOLECULAR BIOLOGY

·  Hematuria is the most common presenting symptom in bladder cancer and should in all cases be investigated

Strong recommendation, High grade evidence (4).

·  The diagnosis of bladder cancer is based on cystoscopic examination of the bladder and histological evaluation of tissue obtained either with cold-cup biopsy or TURBT. Complete resection of all tumour tissue should be achieved when possible. Muscle tissue should be included in the biopsies, except when a Ta/LG  is expected

Strong recommendation, High grade evidence (4).

·  Cross-sectional upper tract imaging (CT/MRI urography) is recommended to screen for synchronous UTUC, in cases of HG bladder cancer

Conditional recommendation, moderate grade evidence (5).

·  Pathological diagnosis should be made according to latest WHO classification

Strong recommendation, moderate grade evidence (6).

·  In addition to stage and grade, presence and percentage of variant histology, lymphovascular invasion and presence of muscularis propria should be reported

Strong recommendation, High grade evidence (6).

·  Urine cytology can facilitate the diagnosis of HG UC but cannot be used as the primary method of histological diagnosis

Conditional recommendation, moderate grade evidence (7).

2.  STAGING AND RISK ASSESSMENT

Staging of NMIBC

·  Patients with NMIBC are classified into four risk categories based on tumor characteristics (low , intermediate , high  and very-high-risk) as shown in table 1.

Strong recommendation, high grade evidence (9,10).

Regional and distant staging of MIBC

·  In patients with invasive disease (>T1), regional and distant staging should be carried out with further imaging studies such as contrast-enhanced CT of chest-abdomen-pelvis or MRI of abdomen/pelvis combined with chest CT.

Strong recommendation, moderate grade evidence (11).

·  FDG-PET-CT may aid in the detection of LN and distant metastases, and in cases with impaired renal function.

Conditional recommendation, low grade evidence (12).

3. MANAGEMENT OF LOCAL/LOCOREGIONAL DISEASE

Treatment of NMIBC

·  In patients with low-risk NMIBC and those with small papillary recurrences, detected >1 year after the previous tumor, single, immediate, intravesical chemotherapy instillation, such as mitomycin C or gemcitabine, is recommended, in combination with continued cystoscopic surveillance.

Strong recommendation, high grade evidence (13,14)

·  In patients with intermediate-risk NMIBC, additional courses of intravesical therapy are recommended, and is consisting of either instillations of Chemotherapy for a maximum of 1 year, or 12 months of BCG instillation therapy with six BCG instillations at weekly intervals, followed by three BCG instillations each at 3, 6 and 12 months.

Strong recommendation, high grade evidence (15).

·  In patients with high-risk NMIBC, full dose intravesical BCG for 1-3 years (at least 1 year) is recommended with induction as previously mentioned for 6 weeks followed by instillations at 3, 6, 12, 18, 24, 30 and 36 months.

Strong recommendation, high grade evidence (16).

·  Planned cystoscopic surveillance per high risk NMIBC schedule should be performed.

Strong recommendation, high grade evidence (17)

·  In case of very high risk or BCG unresponsive, radical cystectomy could be offered.

      Conditional recommendation, moderate grade evidence (17).

Treatment of MIBC

·  RC with standard PLND and protection of small intestine is the standard treatment of MIBC T2-T4a, N0 M0.

Strong recommendation, high grade evidence (18).

·  Patients with radiological suspicious node-positive disease (cN1) should be considered for preoperative platinum-based chemotherapy, however surgery can be offered in selected cases (e.g. unfit for systemic therapy, patient preference)

Strong recommendation, moderate grade evidence (19-21).

·  Organ-preservation therapy with radiotherapy, as part of multimodal schema for MIBC, is a reasonable option for patients with solitary tumors <7cm with no or unilateral hydronephrosis, and no extensive carcinoma in situ, also for patients seeking an alternative to RC and those who are medically unfit for surgery

Conditional  recommendation, moderate grade evidence (22).

·  Contemporary organ-preservation protocols should utilize tri-modality combination of TURBT, radiotherapy and chemotherapy.

Strong recommendation, moderate grade evidence (23).

·  Following completion of bladder preserving therapy, clinicians should perform regular surveillance with computed tomography (CT) scans, cystoscopy, and urine cytology.

Strong recommendation, moderate grade evidence (23).

·  Three to four cycles of cisplatin-based neoadjuvant chemotherapy should be given to MIBC.

Strong recommendation, high grade evidence (24-28).

·  The use of adjuvant cisplatin-based Chemotherapy in patients with pathological T3/T4/N+ who did not receive neoadjuvant therapy should be considered.

Strong recommendation, moderate grade evidence (27).

·  ddMVAC with growth factor support is the preferred regimen in the neoadjuvant setting, however Gemcitabine and cisplatin is a reasonable alternative

Strong recommendation, moderate grade evidence (27).

·  Carboplatin should not be substituted for cisplatin in the perioperative setting

 Strong recommendation, moderate grade evidence (29)

·  For patients who are not candidates for cisplatin , there are no data to support a recommendation for perioperative chemotherapy

Strong recommendation, moderate grade evidence (29)

·  Standard radical cystectomy with curative intent need to obtain negative margins and should include removal of the bladder, prostate, and seminal vesicles in males; bladder in females and should consider removal of adjacent reproductive organs based on individual disease characteristics. Bilateral pelvic lymphadenectomy should include removal of a minimum, the external and internal iliac and obturator lymph nodes.

Strong recommendation, moderate grade evidence (30)

·  Indications of adjuvant radiotherapy after cystectomy:

     -P T3 / T4 MIBC

     -Pathologically node positive

     -Positive margins 

Strong recommendation, moderate grade evidence (31)

·  Postoperative adjuvant RT : Treatment field should encompass areas at risk for harboring residual microscopic disease based on pathologic findings at resection and include resection bed, and  lymph nodes. Areas at risk for harboring residual microscopic disease should receive 45–50.4 Gy EBRT. Involved resection margins and areas of extranodal extension should be boosted to 54–60 Gy if feasible based on normal tissue constraints. Areas of gross residual disease should be boosted to 66–70 Gy, if feasible based on normal tissue constraints. Concurrent chemotherapy with regimens used for bladder cancer can be considered for added tumor cytotoxicity

Strong recommendation, moderate grade evidence (32)

 4- Treatment of advanced/metastatic disease

First line systemic therapy

·  For Cisplatin eligible patients, gemcitabine and cisplatin or dd-MVAC (with growth factor support) regimens should be used.

Strong recommendation, high grade evidence (33-38).

·  For Cisplatin ineligible patients, gemcitabine and carboplatin regimens should be used.

Strong recommendation, high grade evidence (39).

Second and subsequent lines of therapy

·  Patients with good PS 

Second and subsequent lines of therapy should include either single agents as gemcitabine, paclitaxel, or docetaxel, or combination regimens as Gemcitabine and paclitaxel, or Ifosfamide, doxorubicin, and  gemcitabine   or other combinations

Strong recommendation, moderate grade evidence (40,41).

·  In patients with progression free survival > 12 months after platinum (cisplatin or carboplatin), consider re-treatment with platinum if the patient is still platinum eligible

Conditional recommendation, moderate grade evidence (40,41).

• Palliative RT can be offered for palliation (bleeding, pain).

Strong recommendation, moderate grade evidence (42)

➡️ Clinical indicators for monitoring 

See Annex 4 

➡️ Research Gaps 

•  Evaluation of real world data on the use on new targeted and immune-therapeutic agents in bladder cancer in Egypt.

•  Cost effective analysis of new therapeutic agents in Egypt.

•  Define the molecular biologic profiles of our patients with mixed and variant tumors.

➡️ Update of the guideline

•  This guideline will be updated whenever there is new evidence.