Treatment - Upper Tract Cancers

• Superficial disease
  • Transurethral resection of bladder tumor. As described in the staging section, this is the foundation of therapy for this condition. Tumor seeding during resection a concern. May be minimized by immediate instillation of intravesical chemotherapy after TUR.
  • Laser photocoagulation. The neodymium-yttrium-aluminum-garnet [nd-YAG]. Ablates tissue, therefore no pathology. Less painful and less bleeding. Appropriate for medically compromised patients
  • Intravesical Chemotherapy
    • Surface contact with chemotherapeutic agents to decrease recurrence. No evidence of inhibiting tumor progression.
    • Contemporary agent is mitomycin C 40 mg [1mg/ml] given weekly for 6 weeks. Decreases recurrence approximately 17% some effect with CIS. Few systemic side effects due to high molecular weight. Palmar rash and bladder contraction in 1% of patients
    • Alternate agents include Valrubicin, Classic agent Thiotepa associated with myelosupression due to low molecular weight and systemic absorption.
  • BCG Immunotherapy
    • Attenuated strain of m.bovis that elicits a Th-1 response in the bladder . BCG contact with tumor cell through classic an novel receptors critical in this process. IL-12 and interferon gamma also up-regulated.
    • Indicated for treatment of residual papillary TCC and CIS, prophylaxis of Ta and T1 disease and chemotherapy failures.
    • Contraindicated in immunosuppressed, immunocompromised, poor functional reserve patients and those with hepatic insufficiency.
    • Principle therapy for CIS 76% response, eradicates residual papillary disease in 45-60 percent of patients, and decreases recurrence by 20-65%.
    • Side effects include bladder irritation, low grade fever, BCG osis [need antitubercular therapy], rarely BCG sepsis or bladder contracture.
    • Can be given weekly for 6 weeks with booster administration every 6 months [3 weekly courses]. Optimal course administration not known.
    • Probably provides advantage in preventing progression. Duration of effect uncertain.
    • Maintenance therapy decreases recurrence but at cost of additional side effects.
    • Persistence or recurrence of disease through treatment suggests need for aggressive therapy [cystectomy]
    • Combination of BCG with interferon alpha2b suggests additive effect . Subject of several large scale trials.
  • Monitoring response to intravesical treatment.
    • No evidence-based schedule exists. Reasonable approach is cystoscopy with cytology every 3 months for one year, every 6 months for one year and yearly thereafter with intermittent upper tract monitoring. BCG patients are at higher risk for upper tract lesions. T1 patients should continue on q6 months evaluation. With consideration for occasional cross sectional imaging as well.
    • Tumor markers. Tumor markers such as BTA and NMP-22 , Ha-HAase, and Immunocyte, may provide additional help in extending the cystoscopy interval or predicting early failure. Problems with inflammation affect classic sensitivity analysis. Hazard analysis or neural networks may have some role. Genomic based markers such as microsatellites or FISH {urovysion] may prove useful in the future.
• Muscle Invasive Disease
  • Radical Cystectomy. This is the standard of care in treating muscle-invasive bladder cancer. A radical cystectomy entails en bloc removal of the bladder, prostate, seminal vesicles, and proximal urethra. Indications for radical cystectomy include muscle invasion, low-stage tumors that are unresectable or multicentric, high-grade tumors associated with CIS, and rapidly recurring multifocal tumors or CIS after transurethral resection and intravesical therapy. Patients with high grade superficial disease who do not respond to therapy should be offered cystectomy rather than repeated courses of intravesical treatment. In men cystoprostatectomy with bilateral pelvic lymph node dissection is the standard treatment. Distal urethral involvement occurs more often in patients with prostatic urethral involvement, yet this is less often seen when a orthotopic diversion is employed as the method of urinary diversion. In women a cystectomy as well as a total abdominal hysterectomy and bilateral salpingo-oophorectomy is performed. Five year survival for organ confined disease is 75-90 percent, local extension 45-60 %, and low volume node positive disease 20-35%.
  • Urinary Diversion. This is an integral part of the lower tract reconstruction. Major objectives are the creation of a low pressure, non obstructed system
    • Non-continent diversion consists of the anastomosis of the ureters to a loop of bowel which is then brought through the abdominal wall where a stoma is created and urine drained in an external appliance. The classic diversion is the ileal loop.
    • Continent diversion
      • Cutaneous diversion. Construction of a continent reservoir from a large segment of bowel which exits at the skin to a flat stoma. This is emptied by intermittent clean catheterization.
      • Orthotopic diversion. Construction of a continent reservoir from a large segment of bowel which is anastomosed to the urethra. Urine drainage occurs through the urethra by relaxation of the pelvic floor muscles.
    • Partial Cystectomy.
      • Patients with a small lesion usually in the dome or posterior portion of the bladder may undergo removal of this lesion with a 1-2 cm margin. General outcomes are usually lower than those seen in patients who undergo cystectomy. Applicable to 5% of patients with invasive disease.
    • TUR resection.
      • Applicable to select patients generally with compromised performance status and discrete lesions.
    • Radiation Therapy. Overall response rates in the 20-40 range. Less effective than surgery stage per stage
    • Combined modality therapy. Combination of TUR, radiation, and systemic chemotherapy.
      • Cam be effect in low volume disease without evidence of urinary obstruction. No comparative data to cystectomy
    • Chemotherapy. Platinum based chemotherapy elicits a response in 40-70 percent of patients with advanced disease which may develop in up to 50% of cystectomy patients. The Methotrexate, Vinblastine, Adriamycin, Cisplatinum combination [MVAC] evolved as the early standard. Slight but significant advantage over platinum alone.
      • Taxol plus platinum [carboplatinum] developed. Useful in renal insufficiency
      • Gemcitabine shown effective in single agent and platinum combination with less side effects than MVAC.
      • Role for adjuvant therapy suggested but not proven by data. Tumor marker [p53] studies evaluating role of adjuvant therapy in T2 disease.
      • Several neoadjuvant studies are negative or slightly positive. It is not a standard of care but may be offered.
    • Palliative Therapy. Aggressive therapy is occasionally indicated without intent to cure. Intractable hemorrhage or dysuria can be managed with salvage cystectomy.
    • Patient follow up after cystectomy
      • Although there are no established guidelines for surveillance after cystectomy, a reasonable schedule proposed by the Memorial-Sloan Kettering Cancer Center group includes:
        • History and physical examination (H&P)
        • Chest x-ray
        • Urine cytology
        • Serum laboratories (CBC, SMA-6, and alkaline phosphatase) every 3 months for 1 year, every 4 months for 2 years, and then every 6 months thereafter. In addition, they recommend yearly cross-sectional imaging (CT scan or MRI) and intravenous urography to rule out visceral metastases, lymphadenopathy, ureteral obstruction, and upper tract recurrence.
      • 10 percent of patients will develop a urethral recurrence after cystectomy
        • Patients who do not meet the criteria for urethrectomy at the time of cystectomy will need life-long follow-up.
        • An intact urethra is best monitored by routine urethral cytology performed 4 to 8 weeks after cystectomy, with decreasing frequency thereafter. This is most important early on because most urethral recurrences will manifest in the first 3 years after cystectomy.
        • Patients with positive cytology, hematuria, or symptoms should undergo urethroscopy. In the case of a urethral recurrence after an orthotopic continent urinary diversion, patients should undergo urethrectomy with some form of urinary diversion.
      • Swanson and colleagues at M.D. Anderson Cancer Center proposed a cost-effective follow-up schedule based on pathologic stage, given that 5-year recurrence rates for pT1, pT2, and pT3 disease were 5, 20, and 40 percent, respectively.
        • As no patients with pathological stage TI disease developed pelvic recurrences, they recommend a yearly H&P, laboratories (CBC, SMA-6, liver function tests), upper tract evaluation (intravenous urogram, loopogram, or renal ultrasound), and urine cytology.
        • Patients with pathological stage 2 disease undergo an H&P, laboratories, and CXR every 6 months for 3 years, then yearly.
        • Urine cytology and upper tract imaging (intravenous urogram or renal ultrasound) are recommended on a yearly basis.
        • Patients with pathological stage 3 disease undergo the same surveillance as patients with pT2, with the addition of abdominal CT scans at 6 months, then yearly.
• Metastatic Disease
  • Almost 50 percent of patients with muscle-invasive TCC will suffer a distant or local recurrence of disease.
  • The classic therapy regimen methotrexate, vinblastine, adriamycin, and cis-platinum (MVAC) can effect 50 to 70 percent response rates but less than 15 percent sustain complete responses.
  • Other agents such as paclitaxel, carboplatin, and gemcitabine are also being studied.
  • The role of molecular markers such as p53 in directing or predicting response to chemotherapy is being actively evaluated.

References

• Droller MJ: Bladder: Anatomical overview in surgical management of urologic disease: An anatomic approach, MJ Droller, St. Louis, Mosby Yearbook, p 575, 1992.
• Herr HW, Schwalb DM, Zhang ZF, et al: Intravesical bacillus Calmette-Guerin therapy prevents tumor progression and death from superficial bladder cancer: Ten-year follow-up of a prospective randomized trial. J Clin Oncol 13:1404, 1995.
• Lamm DL: Complications of bacillus Calmette-Guerin immunotherapy. Urol Clin North Am 19:565, 1992.
• Malkowicz SB: Superficial bladder cancer: The role of molecular markers in the treatment of high-risk superficial disease. Semin Urol Oncol 15:169-178, 1997.
• Messing EM, Catalona W: Urothelial tumors of the urinary tract. In: Campbell's Urology 7th ed. PC Walsh, AB ED Vaughan, AJ Wein, Vol 3, Chap 77, 2327, 1998.
• Spruck CH, Ohneseit PE, Gonzalez-Zulueta M, et al: Two molecular pathways to transitional cell carcinoma of the bladder. Cancer Res 54:784-788, 1994.