AUA & ASCO & ASTRO & SUO: Muscle-invasive Bladder Cancer (2020)

See AUA Muscle-invasive Bladder Cancer Guidelines 2020

See CUA Muscle-invasive Bladder Cancer Guidelines 2019

Includes literature search up to May 2020

*****All of the information below is contained in the more comprehensive Muscle-Invasive Bladder Cancer Chapter Notes*****

Diagnosis and Evaluation

UrologySchool.com Summary

• History and Physical exam
  • Exam under anesthesia at time of TURBT for a suspected invasive cancer
• Imaging (2):
  1. Regional: CT abdomen/pelvis
  2. Distant: Chest (CT or CXR)
• Labs (3):
  1. CBC
  2. Liver function tests
  3. Renal function
• Other (1):
  1. TURBT pathology

History and physical exam

• Examination under anesthesia
  • Performed at the time of TURBT for a suspected invasive cancer
  • Provides 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

• Goals of imaging in MIBC are to determine:
  1. Feasibility and safety of removing of the bladder
  2. Presence of hydronephrosis
  3. Presence of upper tract disease
  4. Local extent of the disease
  5. Presence of pelvic or retroperitoneal lymph node metastases
  6. Visceral/distant metastatic sites
• Regional
  • Cross-sectional imaging of the abdomen/pelvis with IV contrast (if not contraindicated)
• Metastasis
  • Chest (CT or CXR)
    • Prior smokers may benefit from a chest CT; 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
    • Indications (2):
      1. Elevated alkaline phosphatase
      2. Presence of bone pain symptoms
  • PET imaging
    • Indications (2):
      1. Abnormal chest, abdominal, or pelvic imaging that requires further evaluation
      2. Biopsy of a suspicious lymph node is not feasible

Laboratory

• CBC, liver function tests, and renal function
  • CBC: provides information regarding anemia and possible occult infection
  • Liver function tests and renal function: 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.
    • Other than alkaline phosphatase, liver function tests not further specified.
      • Liver function tests typically include[1]:
        • Alanine transaminase (ALT)
        • Aspartate transaminase (AST)
        • Alkaline phosphatase (ALP)
        • Gamma-glutamyl transferase (GGT)
        • Serum bilirubin
        • Prothrombin time (PT)
        • International normalized ratio (INR)
        • Total protein
        • Albumin

Other

• TURBT pathology
  • Provides information on clinical staging, in addition to EUA
  • If variant histology (e.g., micropapillary, nested, plasmacytoid, neuroendocrine, sarcomatoid, extensive squamous or glandular differentiation) is suspected OR if muscle invasion is equivocal, an experienced genitourinary pathologist should review the pathology
    • Pathologic re-review of cystectomy specimens by experienced genitourinary pathologists may identify variants that alter treatment in up to 33% of patients

Management

Patient counseling

• 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, patients should be counselled regarding complications and the implications of treatment on quality of life (e.g., impact on continence, sexual function, fertility, bowel dysfunction, metabolic problems).
  • Patients with
    • Ileal conduit urinary diversion require external appliances and have risks of leakage or stomal complications.
    • Continent cutaneous reservoirs require self-catheterization for the rest of their lives and have risks of incontinence via their stoma, stricture, pouchitis, pouch stones, and metabolic derangements.
    • Neobladders have risks 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 Complications of Urinary Diversion notes)

Neoadjuvant/adjuvant chemotherapy

• Prior to cystectomy, cisplatin-based NAC should be offered to eligible radical cystectomy patients, utilizing a multidisciplinary approach
• The best regimen and duration for cisplatin-based NAC remains undefined
  • No prospective randomized trials have compared gemcitabine and cisplatin to MVAC
    • Retrospective studies have suggested that there is no difference between the regimens in terms of survival.
  • A retrospective study found that patients who did not receive cisplatin-based chemotherapy or fewer than 3 cycles of chemotherapy had worse outcomes, compared to those that who received ≥ 3 cycles of cisplatin-based NAC, either GC or MVAC regimen at standard dose[2]
• Contraindications to cisplatin-based chemotherapy (5):
  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)
  5. Reduced performance status (ECOG ≥2 or Karnofsky performance status ≤60-70%)
• If ineligible for cisplatin-based NAC, patients 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
• Timing of radical cystectomy after NAC
  • Radical cystectomy is recommended as soon as possible following completion of and recovery from NAC, ideally within 12 weeks (CUA: 4-6 weeks after NAC and no more than 10 weeks), following completion of chemotherapy, unless medically inadvisable.
    • Patients must be medically fit to undergo cystectomy.
    • Optimal timing to proceed with cystectomy after chemotherapy has not been defined.
      • Observational studies that suggest that outcomes may be worse if cystectomy is delayed more than 12 weeks after the completion of 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.
• If small cell/high-grade neuroendocrine MIBC: NAC is preferred over AC
  • Studies support the use of systemic chemotherapy for these histologic subtypes.
• If 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

• Radical cystectomy with bilateral pelvic lymphadenectomy should be offered 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 radical cystectomy, clinicians should remove the bladder, prostate, and seminal vesicles in males and should remove the bladder and consider removal of adjacent reproductive organs based on individual disease characteristics and need to obtain negative margins
  • Radical cystectomy involves removal of the bladder (cystectomy) along with the organs at highest risk of harboring tumors that extend beyond the bladder.
  • In select females with early stage disease and a desire to preserve fertility and/or sexual function, organ preservation may be considered as long as complete tumor resection can be achieved.
    • More emphasis on organ preservation in females compared to 2017 MIBC guidelines.

Urethrectomy

• Indications
  1. All females not receiving neobladder to reduce risk of positive surgical margin or tumor recurrence (different than CUA)
  2. Males with invasive cancer at the apical urethral margin
     • Apical urethral margin assessed with
       • Intra-operative frozen section OR
       • Final pathology of the radical cystectomy specimen
     • Urethrectomy can be performed at the time of cystectomy or delayed

Sexual function preserving procedures

• Should be considered for patients with organ-confined disease and absence of bladder neck, urethra, and prostate (male) involvement.

• Nerve-sparing should be discussed and offered in all patients who desire sexual function preservation and are sexually active, as long as it will not compromise oncologic control.
• Prostate-sparing and prostate-capsule sparing cystectomy in males
  • May be offered to highly select males with negative prostatic urethral and transrectal prostate biopsies in whom fertility and sexual function are important considerations.
  • Nerve sparing procedures in males may offer similar rates of sexual function preservation when compared to prostate-sparing cystectomy.
• Vaginal sparing radical cystectomy in females
  • 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 radical cystectomy.
  • Combined mechanical and pharmacologic prophylaxis is recommended.
    • 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.
• 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 radical cystectomy, 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)
• In patients undergoing an orthotopic urinary diversion, a negative urethral margin must be verified
  • Risk cancer developing in the retained urethral is 1-17%, the majority of which occur within the first 2 years after surgery.
  • 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

• Bilateral pelvic lymphadenectomy must be performed 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, at a minimum, the external and internal iliac and obturator lymph nodes should be removed
  • 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 in MIBC

• A multi-disciplinary team discussion is preferred for patients considering bladder preservation.

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 (4):
  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
• In patients under consideration for bladder preserving therapy, maximal debulking transurethral resection of bladder tumor and assessment of multifocal disease/carcinoma in situ should be performed
  • In multiple prospective trials, the ability to resect all tumor predicted the best response to bladder preserving therapies.
  • Random biopsies may help ensure that there is no associated CIS.
• 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.
• Histological considerations
  • 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.

Multi-modal bladder preserving therapy

• Includes (3):
  1. Maximal transurethral resection of bladder tumor
  2. Chemotherapy combined with external beam radiation therapy
  3. Ongoing cystoscopy to evaluate response
• Radiation sensitizing chemotherapy
  • Should be included when using multi-modal therapy with curative intent.
    • Radiation with concurrent chemotherapy is superior to radiation alone.
  • Several radiosensitizing chemotherapeutic agents have been shown safe and effective for trimodal bladder cancer therapy
    • Various regimens of neoadjuvant, concurrent and adjuvant cisplatin-based regimens (e.g., cisplatin alone, CMV, cisplatin + paclitaxel or cisplatin + gemcitabine) have been studied.
    • Alternatives for cisplatin-ineligible patients include gemcitabine or 5-fluorouracil and mitomycin C.
    • Carboplatin should not be used as a radiosensitizer unless there are contraindications to cisplatin, 5-FU, and gemcitabine.
      • Carboplatin has been found to be inferior to cisplatin in multimodal bladder preserving therapy
• Follow-up
  • 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.
    • No direct evidence to determine optimal frequency of surveillance, published protocols recommend:
      • Cystoscopy: every 3 months during the first year, every 4-6 months in the second, and every 6-12 months thereafter
      • 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 radically cystectomy should not undergo maximal TURBT or partial cystectomy as primary curative therapy
  • Therapies other than radical cystectomy (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
• Patients should be informed that approximately 40% of patients treated in this manner will ultimately require cystectomy and may have an increased risk of bladder cancer mortality.
• For patients with MIBC that have chosen maximal TURBT, no further treatment may be required if they have a tumor that can be macroscopically resected completely, and for which repeat TURBT is negative.
  • Studies have demonstrated that a significant proportion of patients with small MIBC’s who have a negative re-resection may be locally controlled by TURBT.
• For cisplatin-eligible patients with MIBC patients that have chosen partial cystectomy and pelvic lymphadenectomy, perioperative chemotherapy should be offered.

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 radical cystectomy 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 radical cystectomy with bilateral pelvic lymphadenectomy.

Urologyschool.com 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): 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%
    • Cross sectional imaging is preferably with intravenous contrast and delayed images to evaluate the collecting system and also other sites of disease.
    • 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
    • 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 2020 AUA MIBC Guidelines, what are the contraindications to cisplatin-based NAC? What the second-line NAC regimen for those with contraindications to cisplatin-based NAC?
2. As per the 2020 AUA MIBC Guidelines, what is the timing of cystectomy with regard to completion of chemotherapy?
3. As per the 2020 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 2020 AUA MIBC Guidelines, what are the indications for a urethrectomy in patients undergoing RC?
6. As per the 2020 AUA MIBC Guidelines, what are the contraindications to a continent diversion?
7. As per the 2020 AUA MIBC Guidelines, which lymph nodes should be removed at the time of RC?
8. As per the 2020 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 2020 AUA MIBC Guidelines, what is the role of partial cystectomy in the treatment of MIBC and which patients are candidates?
10. As per the 2020 AUA MIBC Guidelines, what are the recommended laboratory investigations during follow-up of RC?

Answers

1. As per the 2020 AUA MIBC Guidelines, what are the contraindications to cisplatin-based NAC? What the second-line NAC regimen for those with contraindications to cisplatin-based NAC?
2. As per the 2020 AUA MIBC Guidelines, what is the timing of cystectomy with regard to completion of chemotherapy?
3. As per the 2020 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 2020 AUA MIBC Guidelines, what are the indications for a urethrectomy in patients undergoing RC?
6. As per the 2020 AUA MIBC Guidelines, what are the contraindications to a continent diversion?
7. As per the 2020 AUA MIBC Guidelines, which lymph nodes should be removed at the time of RC?
8. As per the 2020 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 2020 AUA MIBC Guidelines, what is the role of partial cystectomy in the treatment of MIBC and which patients are candidates?
10. As per the 2020 AUA MIBC Guidelines, what are the recommended laboratory investigations during follow-up of RC?

References

• Chang, Sam S., et al. "Treatment of non-metastatic muscle-invasive bladder cancer: AUA/ASCO/ASTRO/SUO guideline." The Journal of urology 198.3 (2017): 552-559.