Muscle-invasive Bladder Cancer (2017)

See CUA Muscle-invasive Bladder Cancer Guidelines 2019

Diagnosis and Evaluation

• UrologySchool.com Summary
  • H+P, TURBT pathology, EUA, CT abdo/pelvis, chest imaging, CBC, LFTs, Cr

• History and physical exam
• Clinical Staging
  • TURBT pathology
    • An experienced genitourinary pathologist should review the pathology of a patient when variant histology (e.g., micropapillary, nested, plasmacytoid, neuroendocrine, sarcomatoid, extensive squamous or glandular differentiation) is suspected OR if muscle invasion is equivocal
      • Pathologic re-review of cystectomy specimens by experienced genitourinary pathologists may identify variants that alter treatment in up to 33% of patients
  • Examination under anesthesia at time of TURBT for a suspected invasive cancer
    • An exam under anesthesia (EUA) provides valuable information for the clinical staging and resectability of the primary tumor at surgery. This information contributes to the overall determination of clinical stage and assessment of potential benefit of neoadjuvant chemotherapy (NAC). Presence of a large/3-dimensional, residual mass after TURBT (cT3b), invasion of adjacent structures (cT4a), or fixation (cT4b) imply locally advanced clinical stage.
  • Imaging
    • Attempts to determine:
      1. Feasibility and safety of removing of the bladder
      2. Presence of pelvic or retroperitoneal lymph node metastases
      3. Presence of hydronephrosis
      4. Presence of upper tract disease
      5. Local extent of the disease
      6. Visceral/distant metastatic sites
    • Primary
      • Cross-sectional imaging of the abdomen/pelvis with IV contrast (if not contraindicated)
    • Metastasis:
      • Chest
        • Prior smokers may benefit from a chest CT while non-smokers should have a minimum of a chest x-ray (with posterior-anterior and lateral images). Non-smokers also may benefit from CT imaging to evaluate for metastatic cancer.
      • Bone scan
        • In the absence of an elevated alkaline phosphatase, a bone scan need not be performed, but should be performed in patients with bone pain symptoms.
      • PET imaging
        • Should be reserved for patients with abnormal chest, abdominal, or pelvic imaging that require further evaluation, or if biopsy of a suspicious lymph node is not feasible.
  • Laboratory: CBC, LFTs, alkaline phosphatase, and renal function
    • A CBC provides information regarding anemia and possible occult infection
    • The choice of urinary diversion in patients undergoing cystectomy is greatly influenced by metabolic abnormalities, such as acidosis or renal or hepatic insufficiency, and abnormal laboratory values may impact the ability to administer chemotherapy.

Management

• For patients with newly diagnosed MIBC, curative treatment options should be discussed based on both patient comorbidity and tumor characteristics. Patient evaluation should be completed using a multidisciplinary approach.
• Prior to treatment, clinicians should counsel patients regarding complications and the implications of treatment on quality of life (e.g., impact on continence, sexual function, fertility, bowel dysfunction, metabolic problems).
  • Patients who undergo ileal conduit urinary diversion will have to deal with external appliances and potential issues with leakage or stomal complications.
  • Patients with continent cutaneous reservoirs require self-catheterization for the rest of their lives and have the potential for incontinence via their stoma, stricture, pouchitis, pouch stones, and metabolic derangements.
  • Patients with neobladders have a risk of incontinence (especially night-time), bladder neck contractures, voiding dysfunction with retention, and fistula formation
  • Sexual dysfunction, metabolic and nutritional issues can also result from urinary diversions (Recall LSD ORGASMIC from Campbell’s Chapter 97 notes)
• Neoadjuvant/adjuvant chemotherapy
  • Utilizing a multidisciplinary approach, clinicians should offer cisplatin-based NAC to eligible radical cystectomy (RC) patients prior to cystectomy.
    • Contraindications to cisplatin-based chemotherapy (these 4 are included in CUA contraindications, but CUA also includes ECOG ≥2 and untreated infection):
      1. eGFR < 60ml/min (CUA uses cut-off <50)
      2. Heart failure (NYHA Class > 2)
      3. ≥Grade 2 hearing loss (grading based on Common Terminology Criteria for Adverse Events version 4.0)
      4. ≥Grade 2 neuropathy(grading based on Common Terminology Criteria for Adverse Events version 4.0)
  • Patients ineligible for cisplatin-based NAC should proceed to definitive locoregional therapy (same as CUA).
    • Carboplatin-based neoadjuvant chemotherapy should not be used for clinically resectable stage cT2-T4aN0 bladder cancer
  • RC is recommended within 6-8 weeks of completion of chemotherapy (CUA: 4-6 weeks), and no more than 16 weeks (CUA: 10 weeks) following completion of chemotherapy, unless medically inadvisable.
    • There is no prospective data regarding the optimal timing of cystectomy after chemotherapy
    • Clinicians should perform radical cystectomy as soon as possible following a patient’s completion of and recovery from neoadjuvant chemotherapy.
  • Eligible patients who have not received cisplatin-based NAC and have non-organ confined (pT3/T4and/or N+) disease at cystectomy should be offered adjuvant cisplatin- based chemotherapy (same as CUA)
• Variant histology
  • May require divergence from standard evaluation and management for urothelial carcinoma.
    • Studies support the use of systemic chemotherapy in patients with small cell/high-grade neuroendocrine MIBC. For this histologic subtype, NAC is preferred over AC.
    • For other pure non-urothelial histologic subtypes (squamous, adenocarcinoma, sarcomatoid), perioperative chemotherapy is not routinely recommended as they are perceived to generally be chemo-resistant.
• Radical cystectomy
  • Clinicians should offer RC with bilateral pelvic lymphadenectomy for surgically eligible patients with resectable non-metastatic (M0) muscle-invasive bladder cancer.
    • For non-metastatic MIBC, NAC + RC is the standard of treatment
    • Bladder preserving therapy has been associated with decreased survival compared to RC
  • When performing a standard RC, clinicians should remove the bladder, prostate, and seminal vesicles in males and should remove the bladder, uterus, fallopian tubes, ovaries, and anterior vaginal wall in females.
    • RC involves removal of the bladder (cystectomy) along with the organs at highest risk of harboring tumors that extend beyond the bladder.
  • Urethrectomy
    • In men with invasive cancer at the apical urethral margin, a urethrectomy should be performed (immediate or delayed).
      • The apical urethral margin can be assessed with an intra-operative frozen section or final pathology of the radical cystectomy specimen.
    • In women not undergoing reconstruction with a neobladder, a urethrectomy should be performed for in order to reduce the likelihood of a positive surgical margin or tumor recurrence (different than CUA)
  • Clinicians should discuss and consider sexual function preserving procedures for patients with organ-confined disease and absence of bladder neck, urethra, and prostate (male) involvement.
    • In all patients who desire sexual function preservation and are sexually active, a nerve-sparing procedure should be discussed and offered as long as it will not compromise oncologic control.
    • In men, prostate-sparing and prostate-capsule sparing cystectomy may be offered to highly select individuals with negative prostatic urethral and transrectal prostate biopsies in whom fertility and sexual function are important considerations.
    • Nerve sparing procedures in men may offer similar rates of sexual function preservation when compared to prostate-sparing cystectomy (different than Campbell’s).
    • In women, vaginal sparing radical cystectomy can be performed when doing so will not compromise tumor control, such as in the absence of cancer in the trigone or bladder base. Consideration may also be given to preserving the ovaries for hormonal homeostasis, and the anterior vaginal wall and/or uterus may be preserved in the absence of direct tumor extension.
  • Perioperative surgical management
    • Clinicians should attempt to optimize patient performance status in the perioperative setting.
      • Optimizing nutritional status prior to surgery; preoperative carbohydrate loading in order to diminish postoperative insulin resistance
      • Smoking cessation counseling
      • Consider not routinely prescribing a mechanical bowel preparation when only small bowel will be used for urinary tract reconstruction
    • Perioperative pharmacologic thromboembolic prophylaxis should be given to patients undergoing RC.
      • Combined mechanical and pharmacologic prophylaxis is recommended in patients undergoing RC. Strong consideration should be given to initiating pharmacologic prophylaxis just prior to induction of anesthesia; however, the risks of bleeding need be weighed against the benefits of prophylaxis in determining the timing of heparin administration.
      • Perioperative coverage with up to 4 weeks of treatment following surgery may be beneficial.
    • In patients undergoing radical cystectomy μ-opioid antagonist therapy should be used to accelerate gastrointestinal recovery, unless contraindicated.
      • μ-opioid antagonist therapies are contraindicated in patients who have taken opioids for ≥ 1 week prior to surgery
    • Patients should receive detailed teaching regarding care of urinary diversion prior to discharge from the hospital
  • Urinary diversion
    • In patients undergoing RC, ileal conduit, continent cutaneous, and orthotopic neobladder urinary diversions should all be discussed.
      • Absolute contraindications to continent diversion (6):
        1. Insufficient bowel segment length
        2. Inability to perform self-catheterization
           • Due to inadequate motor function or psychological issues
        3. Inadequate renal function (e.g. an eGFR < 45)
           • Increases the risk metabolic abnormalities as a consequence of reabsorption of urine from continent diversions
        4. Inadequate hepatic function
           • Increases the risk metabolic abnormalities as a consequence of reabsorption of urine from continent diversions
        5. Cancer at the urethral margin (specifically for orthotopic neobladder)
        6. Significant urethral stricture disease that is not correctable (specifically for orthotopic neobladder)
    • A negative urethral margin must be verified in patients undergoing an orthotopic urinary diversion
      • The risk of the development of cancer in the retained urethral is reported as between 1-17%, the majority of which occur within the first 2 years after surgery.
      • Reported risk factors include tumor multiplicity, papillary pattern, CIS, tumor at the bladder neck, prostatic urethral involvement, and prostatic stromal invasion. Although prostate involvement is the most significant risk factor for cancer in the urethra, it should not preclude orthotopic diversion, provided that intraoperative frozen section analysis of the urethral margin is without evidence of tumor.
      • Preoperative prostatic urethral biopsies have not proved to be as reliable as urethral frozen sections and should not exclude patients from orthotopic diversion.
  • Pelvic lymphadenectomy
    • Clinicians must perform a bilateral pelvic lymphadenectomy at the time of any surgery with curative intent
      • Bilateral pelvic lymphadenectomy should be performed in ALL patients, including those with unilateral bladder wall involvement, due to documented crossover risk to the contralateral lymphatic chain.
    • When performing bilateral pelvic lymphadenectomy, clinicians should remove, at a minimum, the external and internal iliac and obturator lymph nodes
      • In order to facilitate adequate staging, a standard lymphadenectomy (bilateral external iliac, internal iliac and obturator lymph nodes), at a minimum, needs to be completed with >12 lymph nodes evaluated
      • Submission of separate nodal packets appears to facilitate identification of lymph nodes and is associated with an increased number of reported lymph nodes
• Bladder preservation approaches
  • For those patients considering bladder preservation, a multi-disciplinary team discussion is preferred.
  • Patient selection
    • For patients with newly diagnosed non-metastatic MIBC who desire to retain their bladder, and for those with significant comorbidities for whom radical cystectomy is not a treatment option, clinicians should offer bladder preserving therapy when clinically appropriate
      • Overall, bladder preserving therapy has been associated with decreased survival compared to RC
      • Studies that support bladder preserving strategies, as a general rule, have highly select patient populations;  
    • Ideal characteristics for bladder preservation:
      1. Unifocal tumor
      2. No CIS
      3. No evidence of hydronephrosis
      4. A tumor that can be completely transurethrally resected
      • • CUA also mentions tumour size <5cm, good bladder capacity, and motivated patient
    • Patients with large tumors unable to be resected by TURBT, multifocal CIS, T3/T4 tumors, and/or hydronephrosis are not ideal candidates for any type of bladder preserving therapy. Random biopsies may help ensure that there is no associated CIS.
  • Multi-modal bladder preserving therapy for patients with MIBC
    • Includes:
      1. Maximal transurethral resection of bladder tumor
      2. Chemotherapy combined with external beam radiation therapy
         • Radiation sensitizing chemotherapy regimens should include cisplatin or 5-fluorouracil and mitomycin C.
      3. Ongoing cystoscopy to evaluate response
    • It is unknown how variant histology affects outcomes associated with multi-modal bladder preserving therapy.
    • Patients with adenocarcinomas, sarcomas, and squamous cell carcinomas have not been included in prospective studies of radiation-based bladder preservation and thus should not receive this therapy unless medically unfit for cystectomy.
    • For medically operable patients receiving staged multi-modal therapy, clinicians should offer a mid-course evaluation to allow for the early selection of non-responders before consolidation radiotherapy is given
    • Following completion of bladder preserving therapy, clinicians should perform regular surveillance with CT scans, cystoscopy, and urine cytology
      • Those who are biopsy-proven complete responders to bladder preserving protocols remain at risk for both invasive and non-invasive recurrences as well as new tumors in the upper tracts.
      • Although there is no direct evidence to determine optimal frequency of surveillance, published protocols recommend every 3 month cystoscopy during the first year, every 4-6 months in the second, and every 6-12 months thereafter, and cross-sectional imaging of the abdomen and pelvis and chest imaging every 6 months for the first 2 years
  • Maximal TURBT/partial cystectomy
    • Patients with MIBC who are medically fit and consent to RC should not undergo maximal TURBT or partial cystectomy as primary curative therapy
      • Therapies other than RC (e.g., partial cystectomy, TURBT alone, chemotherapy alone, or radiation alone) and multi-modal bladder preserving therapy are associated with increased risk of all-cause mortality
    • Patients who are unfit for cystectomy and multi-modal bladder preserving therapy may be offered
      • Radical, maximal TURBT alone if they have a tumor that can be macroscopically resected completely, and for which repeat TURBT is negative or
      • Partial cystectomy, bilateral pelvic lymphadenectomy and perioperative chemotherapy for cisplatin-eligible patients
      • If they meet the following criteria:
        1. Accessible tumor location
        2. Size <3cm
        3. No multi-focal CIS
        4. No hydronephrosis
        5. Adequate bladder function
        6. No residual T1 or higher stage disease
  • Primary radiotherapy
    • For patients with MIBC, clinicians should not offer radiation therapy alone as a curative treatment
  • Bladder preserving treatment failure
    • Patients who are medically fit and have residual or recurrent muscle-invasive disease following bladder preserving therapy should be offered RC with bilateral pelvic lymphadenectomy
      • ≈30% of those selected for treatment by multi-modal bladder preserving therapy will have an invasive recurrence
    • In patients who have a non-muscle invasive recurrence after bladder preserving therapy, clinicians may offer either local measures, such as TURBT with intravesical therapy, or RC with bilateral pelvic lymphadenectomy.

My summary of AUA Treatment of MIBC

• First-line: NAC + RC
• Second-line: RC +/- AC
• Third-line: multi-modal therapy
• Fourth-line: maximal TURBT or partial cystectomy if they meet certain criteria

Patient surveillance and follow-up

• Imaging
  • Chest and cross-sectional imaging of the abdomen and pelvis (CT or MRI) should be obtained at 6-12 month intervals for 2-3 years and then may continue annually
    • The overall prevalence of upper tract urothelial carcinoma after cystectomy ranges from 1-6%
    • Imaging beyond 5 years should be based on shared decision making between the patient and clinician.
• Laboratory values and urine markers
  • Following therapy for MIBC, patients should undergo laboratory assessment of electrolytes, renal function, +/- vitamin B12 at 3-6 month intervals for 2-3 years and then annually thereafter
    • Patients may experience metabolic derangements and declines in renal function over time associated with urinary diversion
    • Vitamin B12 levels should be assessed in patients with resection of > 60 cm of ileum and in those patients in whom the terminal ileum is utilized as there is an increased risk of deficiency and consequent neurological damage
    • Routine frequent CBC and liver function testing for cancer surveillance has not been validated
    • There is insufficient data to support the routine use of cytology or urine-based tumor markers in detection of upper tract urothelial cancers; urine collected from intestinal urinary diversion or previously irradiated bladders may contain desquamated intestinal epithelial cells or atypia due to therapy, which may lower the diagnostic specificity.
  • In patients with a retained urethra following radical cystectomy, the urethral remnant should be monitored for recurrence
    • Urethral wash cytology may be a valuable tool in higher risk patients with a retained urethra. This should be considered during follow up, and patients should undergo physical examination of the urethra and discussion of any urethral symptoms such as urethral discharge or spotting.

• Patient survivorship
  • Clinicians should discuss with patients how they are coping with their bladder cancer diagnosis and treatment and should recommend that patients consider participating in a cancer support group or consider receiving individual counseling.
  • Clinicians should encourage bladder cancer patients to adopt healthy lifestyle habits, including smoking cessation, exercise, and a healthy diet, to improve long-term health and quality of life.

Questions

1. As per the 2017 AUA MIBC Guidelines, what are the contraindications to cisplatin-based NAC? Do these differ from the CUA MIBC Guidelines? What the second-line NAC regimen for those with contraindications to cisplatin-based NAC?
2. As per the 2017 AUA MIBC Guidelines, what is the timing of cystectomy with regard to completion of chemotherapy?
3. As per the 2017 AUA MIBC Guidelines, who should receive adjuvant chemotherapy after RC?
4. At the time of RC, which organs are removed with the bladder?
5. As per the 2017 AUA MIBC Guidelines, what are the indications for a urethrectomy in patients undergoing RC?
6. As per the 2017 AUA MIBC Guidelines, what are the contraindications to a continent diversion?
7. As per the 2017 AUA MIBC Guidelines, which lymph nodes should be removed at the time of RC?
8. As per the 2017 AUA MIBC Guidelines, what are the ideal characteristics for bladder preservation in the treatment of MIBC? What is the recommended bladder preservation treatment method?
9. As per the 2017 AUA MIBC Guidelines, what is the role of partial cystectomy in the treatment of MIBC and which patients are candidates?
10. As per the 2017 AUA MIBC Guidelines, what are the recommended laboratory investigations during follow-up of RC?

Answers

1. As per the 2017 AUA MIBC Guidelines, what are the contraindications to cisplatin-based NAC? Do these differ from the CUA MIBC Guidelines? What the second-line NAC regimen for those with contraindications to cisplatin-based NAC?
2. As per the 2017 AUA MIBC Guidelines, what is the timing of cystectomy with regard to completion of chemotherapy?
3. As per the 2017 AUA MIBC Guidelines, who should receive adjuvant chemotherapy after RC?
4. At the time of RC, which organs are removed with the bladder?
5. As per the 2017 AUA MIBC Guidelines, what are the indications for a urethrectomy in patients undergoing RC?
6. As per the 2017 AUA MIBC Guidelines, what are the contraindications to a continent diversion?
7. As per the 2017 AUA MIBC Guidelines, which lymph nodes should be removed at the time of RC?
8. As per the 2017 AUA MIBC Guidelines, what are the ideal characteristics for bladder preservation in the treatment of MIBC? What is the recommended bladder preservation treatment method?
9. As per the 2017 AUA MIBC Guidelines, what is the role of partial cystectomy in the treatment of MIBC and which patients are candidates?
10. As per the 2017 AUA MIBC Guidelines, what are the recommended laboratory investigations during follow-up of RC?