Bladder Cancer

C ontemporary

DAVID BELL, MD, FRCSC YVES FRADET, MD, FRCSC SUMMARY Bladder concer is currently the fith most common cancer in Western society, and Its inddence oppears to be increosing. Importont advonces hove recently VER THE LAST FEW DECADES prevalence is found in those aged 60 to 70 occurred in both diagnostic and theropeutk approaches to there has been a tremendous years, although tumors have been identi- bladder neoplasms. expansion in our knowledge fied in all age groups. Presentotion Is not unique, about carcinoma ofthe blad- In North America, the factors most and physician aworeness is der. New insights into patho- commonly associated with the develop- important to identify potints genesis, including mechanisms and ment of bladder cancer include smoking who are at risk for bladder characteristics of malignant change, as well and occupational exposure to carcinogens. neoplasio and consequently as a clearer definition of the natural history Smoking has a clear epidemiological asso- require further investigation. of bladder cancer, have led to improved ciation with bladder cancer, although the A diagnostk approoch and management ofthe patient with bladder car- association is weaker than that with tobac- contemporary manogement are cinoma in both diagnosis and therapy. This co and carcinoma of the lung. The risk of riscussed. article reviews contemporary knowledge tumor development is proportional to the RESUME about the diagnosis and management ofpa- degree and duration oftobacco use.3 Occu- Dons les pays ocddentaux, le tients with bladder cancer. pational exposure to aromatic amines and cancer de la vessle occupe aniline dyes, most commonly found in the octuellement la cinquieme Epidemiology rubber, paint, and textile industries, has place sur la Iste des cancers The incidence and prevalence of bladder been associated with the development of les plus frequents et son incidence semble ougmenter. cancer appears to be increasing, with a cur- bladder tumors. The latency period be- D'importants progres sont rent annual incidence of 16 in 100 000 pop- tween exposure and development of blad- ricemment survenus dons les ulation.' Bladder cancer is currently the der tumors is often long, usually in excess approches diagnostiques et fifth most common cancer in Western soci- of 2 decades. Approximately half of blad- theropeutiques des neoplasies ety. It is three times more common in male der carcinomas in North America are be- veskoles. Puisque le mode de patients, although the incidence in female lieved to be secondary to tobacco use and pr6sentation n'est pas patients is increasing dramatically; presum- approximately one quarter to be related to unique, les m6decins doivent ably this increase is related to increased cig- occupational carcinogens.4 donc etre attentlfs pour bien arette smoking among women.2 Peak Other factors proposed to be of etiologic identifir les patients a risque de cancer de la vessie et importance include excessive coffee con- necessitont per consequent Dr Bell is a Fellow i Um-oncologv at dhe LavaI sumption, aluminum exposure, analgesic une investigation plus Uniersiy Cancer Researkh Cenb, L'Hotel-Dieu de abuse (ie, phenacetin derivatives), consump- poussee. L'artkie discute Qfbec, Qe., mad is a mfellw9ofawfeldowslt d tion of brachen fern (fiddleheads), exposure d'une opproche diagnostique fimn the Candian Aiwyu Fondatio. Dr Fradet is to motor vehicle exhaust fumes, and use of et du traitement an Associate Pmfessor at dhe Deparment ofSwgery and artificial sweeteners, although this last factor contemporoin de cette an Um-oncolgist at the Laval Unversity Gacr is controversial.4 Factors causing bladder in- pathoogie. Researh Cen, L'H6tel-Dieu de Quibec. He is also a flammation, such as recurrent urinary tract Gmnfm Pkm 1991;37:1469-1477. scetist with the Medial R h Conil of Canada. infections, chronic urinary catheterization,

Canadian Family Physician VOL 37: June 1991 1469 urinary stasis, and long-standing urinary ofthe transitional epithelium has occurred. calculi, have been associated with increased Dysplasia of the bladder epithelium com- propensity for tumor formation. In other monly precedes tumor formation. _ _I geographic regions, particularly in the Several patterns of tumor morphology may be encountefed. Tumors can exhibit Table 1. SYMPTOMS AND INVESTIGATIONS FOR an exophytic or papillary growth pattern, CARCINOMA OF THE BLADDER most commonly manifested by tumors of low histologic grade. They can also appear solid and nodular, which usually indicates high-grade and invasive disease (Figure 1). Carcinoma in situ exhibits a flat intraepi- thelial growth pattern and is an ominous finding, as it can rapidly progress to invasive or metastatic disease. An important feature in malignant transformation of bladder epithelium is related to the manner of carcinogen exposure. Urinary borne carcinogens evoke a Urine culure "field change" of the urothelium. Thus, Urine bladder mucosa distant from the site of cytology identified tumor can exhibit dysplasia or L Intravenous pyelogram i carcinoma in situ, explaining the finding of Urologk referral tumor recurrence or new tumor formation I so common in patients with bladder carci- Middle East and in Southeast Asia, infec- noma. tion with Schistosoma haematobium is a well- Pathologic staging ofbladder carcinoma established etiologic factor in the develop- is important in predicting the clinical ment of squamous cell carcinoma and course and for selecting the appropriate appears to be related to a chronic inflamma- therapy.5 Most important in this consider- tory process. Previous pelvic radiotherapy ation is the depth oftumor penetration into and past cyclophosphamide administration the bladder wall. The grade oftumor is also have also been associated with tumor important in prognosis (Fzgure 2). development.2 The spectrum of urothelial neoplasia appears to be one of a heterogenous dis- Pathology ease.6 On one end ofthe spectrum is a do- The epithelial lining of the urinary tract cile superficial papilloma and at the other from the renal pelvis to the prostatic ure- end a highly aggressive carcinoma. Most thra is a transitional cell epithelium or uro- (75%) tumors are superficial papillomas. thelium. The entire urothelium is exposed Recurrence is common in this population, to carcinogens within the urine, and thus occurring in 50% to 60% of patients, but tumors can arise on any level ofthe urinary progression to invasive disease is rare, oc- tract. The vast majority (more than 95%) curring in only 10% of cases. Twenty-five occur within the urinary bladder, where the percent of patients have invasive bladder duration of carcinogen exposure is pro- cancer, of which 75% have no history of longed during urine storage. Patients with previous tumor. Many ofthese patients will bladder diverticuli, who have poor empty- subsequently be found to have clinical or ing ability resulting in urinary stasis, have microscopic metastatic spread. increased propensity for tumor formation. Thus clinical and pathologic evidence Only 5% to IO0% oftumors occur within the suggests the existence of two relatively dis- renal pelvis, ureter, or urethra. tinct diseases - a superficial disease prone In North America, the most common to recurrence and rarely to progression, histology identified is transitional cell carci- and a highly aggressive invasive entity ac- noma (90%).2 Squamous carcinoma (6% counting for more than 85% oftransitional incidence) and adenocarcinoma (4% inci- cell carcinoma deaths. These two popula- dence) can arise ifprior metaplastic change tions overlap, and it is here that a signifi-

1470 Canadian Family Phys-icanVOL 37:,June 1991 cant research effort is focused to identify tion of tireeric obstruction in patients with superficial tumors that might exhibit a high bladder cancer, hut resoluition is limited in malignant potential.6 the imaging of intravesical neoplasms.

Clinical presentation Figure 1. TUMOR MORPHOLOGY: A) LOW-GRADE Hematuria is the most common present- SUPERFICIAL CARCINOMAS EXHIBITING A ing symptom of bladder carcinoma. He- PAPILLARY GROWTH PATTERN maturia can be microscopic or gross, although the latter most strongly suggests the diagnosis. It can be episodic and, at times, severe resulting in clot formation. The hematuria is classically unassociated with other vesical symptoms, and thus hematuria ofany magnitude requires further urologic investigation. A second symptom complex associated with bladder neoplasia is irritative voiding symptoms. Dysuria, frequent voiding, urgency to void, and suprapubic discomfort with or without hematuria suggest the possibility of bladder tumor, especially in the absence of a positive urine culture. Patients present- ing with these symptoms commonlv are B) HIGH-GRADE TUMOR EXHIBITING NODU- found to have carcinoma in sitU or invasive LAR GROWTH PATTERN: ,Viote multjfocal tumors in A. disease upon urologic evaluation (Tahle 1). Higk grade tumors (B) often manifest musck inva.son. Other uncommon modes of presentation include pelvic pain from local invasion, bladder outlet obstruction, and systemic symptoms ofazotemia secondary to bilater- al ureteric obstruction. Findings of lymphatic obstruction, stich as edema of the genitalia or of the lower extremities, can also occur in patients with lymphatic metastases. Patients with advanced disease can also present with symptoms related to bone, liver, or pulmonary metastases with or without concurrent urinary symptoms.

Diagnosis The presence ofhematuiia or irritative voiding symptoms requires a thorough urologic investigation involving radiographic and endoscopic procedures. The imaging proce- Endoscopic asscssmcnt is a mainstay in dure most commonly performed is the the diagnosis of bladder cancer. Detcrmi- intravenous pyelogram. Radiographic find- nation of tumor number, size, and mor- ings suggesting the diagnosis of urothelial phology and of the extent of local invasion cancer include "filling defects" wvithin the re- can be obtained at the time of cystoscopy. nal pelvis, ureter, or bladder; ureteric ob- Evaluation ofthe normal vesical mucosa by struction; or deformity ofthe bladder Nwall on random biopsy is performcd to exclucde cystogram views. The finding ofrenal calcuili neoplastic field changes. or a renal mass lesion does not exclude the Urinary cytology can be performed on diagnosis of bladder cancer in patients pres- turine or barbotage specimens obtained at enting with hematuria, and endoscopic the time ofendoscopy. Cytology is a sensitive assessment is indicated in these patients. Ul- test for high-grade urothelial tuimors, wkith uip trasound is occasionally useful in the evalua- to 80% ofhigh-grade tumors exfoliating cells

(anadian Family PhvsiCian V013.7: 7une 1991 1471 Fvgure 2. STAGING IN BLADDER CARCINOA BASED ON PATHOLOGIC ASSESSMENT OF THE DEPTH OF BLADDER WALL PENETRATION: Superficial tumors involve mucosa or lamina propria only; muscularpenetration denotes invasive disease

TIS TA Ti T2 T3a T3b CIs 0 A BI B2 C

mucosa lamina propria

muscle layer perivesical fat

Stage D = lymph node (JVs±) or visceral metastases (M±)

Figure 3. MANAGEMENT OF BLADDER CANCER

SUPERFICIAL BLADDER CANCER (SUSPECTED)

Endoscopy

Primary Recurrent

Transurethral resection Transurethral resection

Grade Superficial (arcinoma in situ Invasive Low High Carcinoma in situ l l l l o | ~~~~~~~~Adjuvatnhtintravesicaltherapy | | RadiclsurgeryRdtlugr cystoscopy Prgrsso

Recurrence | Progression |

1472 Canadian Family Physician VOL 37: June 1991 into the urine. Only 20% of low-grade tu- years, and annual examinations if there is mors are detectable on cytologic assess- no evidence of tumor formation. ment, as morphologic alterations in Transurethral resection or electrofulgu- low-grade urothelial neoplasia can be mini- ration has been the mainstay in treating su- mal, thus resembling normal urothelial perficial tumors and is usually successful in cells. Urinary cytology is, however, a useful tumor control. Lasers have recently been test in the diagnosis ofurothelial cancer and used for fulguration of superficial neo- should be performed in patients with symp- plasms. Laser ablation alone offers no ad- toms suggestive of bladder neoplasia. vantage over transurethral resection; Negative results ofurine cytology do not however, significant developments have oc- exclude the presence of bladder neoplasia, curred in the field of laser surgery. and endoscopic examination is required to Hematoporphyrins are compounds that determine the possible presence of tumor. selectively accumulate in neoplastic tissues. Active urinary tract infection, past pelvic Laser excitation ofthese compounds results in radiotherapy, and urinary calculi can lead the formation of free radicals that cause cell to a false-positive urinary cytologic exami- death. Clinical studies have shown hemato- nation. Occasionally one encounters a pa- porphyrin-laser therapy to be highly effec- tient who has persistently positive results of tive in the treatment of both carcinoma in urinary cytology and normal cystoscopic situ and papillary tumors.7'8 Unfortunately, examinations. This suggests carcinoma in cutaneous uptake of the hematoporphyrin situ or occult neoplasm in the upper tracts. derivative occurs and severe photosensitiv- Random mucosal biopsies of the vesical ity persists for up to 1 month after treat- mucosa and ureteroscopic examination of ment. Severe local symptoms, such as the ureters and renal pelvis are required in dysuria and frequency of voiding, also oc- the evaluation of these patients. cur. With further refinement and development of truly selective porphyrin agents, Management this treatment will be a useful adjunct in the Selection of treatment for patients with management of patients with superficial bladder carcinoma is based on accurate disease. staging at the time of initial presentation A small percentage ofpatients will prog- (Figure 3). Transurethral resection of tumor ress to invasive disease, however, and it is and random mucosal biopsies provide in- difficult to identify patients at risk. Patients sight into the depth of tumor penetration with high-grade tumors, those with multifo- as well as the presence ofdysplastic or ma- cal disease, and those who exhibit lamina lignant changes in the remaining urothe- propria invasion are statistically more likely lium. It must be stressed that bladder to develop muscle invasive disease and thus cancer is a heterogenous disease, and treat- require close observation and, commonly, ment accordingly is dictated by both pre- adjuvant intravesical therapy. Patients who cise endoscopic and pathologic assessment. exhibit rapid tumor recurrence are also candidates for adjuvant therapy. Superficial tumors. Tumors that in- Chemotherapy: Various chemotherapeutic volve only the mucosa or the lamina pro- agents, of which the most commonly used pria mucosae with no evidence of muscle are mitomycin C and doxorubicin, have invasion are classified as superficial tumors. proven effective for both definitive man- Two problems are encountered in the management of superficial tumors and for pro- agement of the patient with superficial phylaxis of tumor recurrence.9 Protocols bladder tumors: tumor recurrence and tu- vary, but typically involve weekly intravesi- mor progression. Management ofthese tu- cal administration of a chemotherapeutic mors involves regular endoscopic agent for 6 to 8 weeks. Monthly mainte- examination. Cytologic examination ofthe nance therapy is occasionally continued. urine alone is not adequate to detect Response rates are in the vicinity of 40% low-grade recurrences, and thus endoscop- to 50% for residual superficial tumor and ic examination is required. The current of 60% to 70% for tumor prophylaxis. protocol is cystoscopic examination every Complications depend on the agent used 3 months for 2 years, twice a year for 2 but include urinary tract infections, chemi-

Canadian Family Physician VOL 37: JUne 1991 1473 1474 Canadian Family Physician VOL 37: June 1991 cal cystitis, bladder contracture, and bone Invasive disease. Management ofpatients marrow depression from systemic absorp- who have an invasive carcmoma requwres tion of the instilled agent. The last compli- more aggressive therapy. Preoperative evalua- cation is most often noted in thiotepa tion using abdominal and pelvic computed to- administration. Systemic chemotherapy mography and exclusion of pulmonary has no role in the management of superfi- metastatic deposits is essential in selecting ap- cial bladder carcinoma. propriate therapy in patients with invasive dis- Immunotherapy: In the early 1970s, atten- ease. Significant advances have occurred in tion was focused on the use ofimmunothera- the management of patients with invasive py for the treatment ofneoplastic disease. In bladder tumors in both surgical and medical 1976, Dr A. Morales and associates'° first re- approaches. ported the use of intravesical BCG vaccine Radical cystectomy: Radical surgery with in the treatment of superficial bladder carci- urinary diversion has been the mainstay in noma. This and subsequent trials have the treatment of muscle invasive disease. shown BCG vaccine to be an effective agent Radical cystoprostatectomy or anterior ex- in preventing the recurrence of superficial enteration (bladder, ovaries, uterus, and bladder tumors in more than 60% of pa- anterior vaginal wall) is indicated in patients.'0" The greatest efficacy of BCG vac- tients with stage B or C disease (tumors in- cine, however, has been in the definitive vading the bladder wall), as well as in management ofcarcinoma in situ. Response patients with superficial bladder cancer ex- rates in the vicinity of 70% have been ob- hibiting rapid recurrence, high-grade tu- served.'0"' This has been of tremendous mors, or carcinoma in situ that has failed clinical importance in view of the ominous intravesical chemotherapy or immunother- prognosis of carcinoma in situ of the blad- apy. This is a major surgical procedure and der. Currently BCG vaccine is the agent of only for candidates who have no evidence choice for adjuvant intravesical therapy. of distant metastatic disease on preopera- The BCG vaccine is administered by in- tive staging or metastatic lymphadenopa- travesical instillation. After assuring sterile thy at the time of exploratory laparotomy. urine, a catheter is placed into the bladder Current surgical techniques and improved and the urine is drained; 120 mg ofBCG vac- operative and postoperative management cine in 50 mL ofsterile water is then instilled. have significantly reduced the morbidity The patient is requested to retain the instilla- and mortality ofthis procedure. Urinary di- tion for 4 hours. Treatments are given for 6 version is required, and this factor is usually to 12 weeks, but occasionally monthly mainte- accepted with reluctance by patients. nance treatments are continued. Treatment is The ideal form of urinary diversion generally well tolerated, but urinary frequency would provide low-pressure storage of a and urgency are common. Febrile episodes large volume of urine and allow voluntary can also occur and, ifprolonged or severe, in- expulsion. Unfortunately, until recently, this dicate the development of systemic Bacille has been difficult to achieve. The most com- Calmette-Guerin infection. Treatment with mon urinary diversions that have been used antituberculin agents, such as isoniazid or ri- are intestinal conduits (eg, ileal or sigmoid). fampin, is indicated in patients who experi- These diversions have been highly successful ence severe febrile reactions or who show but do not provide features of urine storage evidence of hepatic dysfunction and pulmo- or timely expulsion. nary infiltrates.'2 Late complications are rare but include Other immunotherapeutic agents, such renal deterioration from recurrent urinary as interferon and keyhole lympet hemocya- tract infection and subsequent pyelonephri- nin, are currently undergoing clinical trials, tis; renal calculi formation; and ostia prob- but BCG vaccine remains the agent against lems, such as stoma stenosis and skin which their efficacy must be measured. maceration. In the past, ureterosigmoidos- Failure to control superficial disease, tomy was used relying on the anal sphincter manifested by rapid tumor recurrence, de- for continence. Unfortunately, long-term velopment ofhigher grade disease, progres- follow up of these patients has revealed re- sion to tumor stage, or persistent carcinoma nal dysfunction, electrolyte abnormalities in situ, is an indication for radical surgery. from fluid shifts across the colonic mucosa,

Canadian Family Physician VOL 37: June 1991 1475 and, more importantly, development of metastatic disease is currently undergoing ex- adenocarcinoma of the colon. Patients tensive review. Cisplatinum appears to be the who have undergone this procedure re- agent having the greatest effect against transi- quire regular colonic endoscopy to monitor tional cell carcinoma. Large-scale studies of a tumor formation. protocol using methotrexate, vinblastine, Recent surgical advances have led to the adriamycin, and cisplatinum are now under continent urinary diversions. Essentially all way at several centers in Canada and the procedures require formation of a urinary United States. Initial results suggest that ap- reservoir using the small intestine or the as- proximately one third of patients with meta- cending colon. A nonrefluxing ureteric anas- static disease achieve a complete response and tomosis is created. Urine is removed by that one third of patients achieve partial re- catheterization of a continent stoma or by sponse. 16 Duration ofresponse is yet to be de- voiding with abdominal pressure ifthe reser- tenrined, and a recent review reveals that voir is placed in an orthotopic position anas- only 15% of patients might achieve a com- tomosed to the urethra. plete response.'7 Chemotherapy is also cur- Our preferred method ofbladder recon- rently being evaluated with radical surgery in struction is illustrated in Figure 4.13 This adjuvant and neoadjuvant protocols. 18 As sur- technique allows preservation of the exter- vival rates in apparent organ-confined disease nal urinary sphincter, thus allowing volun- with surgery alone reveal only a 50% 5-year tary control and continence. Early results survival rate, it is hoped that surgical and che- from these procedures have been encour- motherapeutic approaches will increase dis- aging, although long-term follow up is re- ease-free survival. quired."3-'5 Both patients and physicians find this to be a more acceptable alternative New frontiers to intestinal conduits and external collec- Extensive research is ongoing in the field tion devices. ofbladder cancer, defining genetic, molec- Partial cystectomy: Excision of the bladder ular, and immunologic characteristics of tumor (with adequate tumor-free margins) urothelial neoplasia. The heterogenous na- alone is rarely indicated. Bladder cancer is ture of this disease demands that investiga- a field disease, and thus epithelium with tors identify factors that might indicate neoplastic potential can remain in vivo. invasive and metastatic potential in other- Also, cystotomy risks extravesical implanta- wise superficial tumors. tion of neoplastic cells, thus potentially en- Immunologic studies have revealed that abling pelvic recurrence. Partial alteration in cellular antigen expression can cystectomy is indicated only in select pa- provide relevant clinical information. Loss tients or as a palliative procedure in patients of blood group antigen expression on neo- with advanced disease and severe local plastic cells has been shown to correlate symptoms, for example, hematuria. with more aggressive neoplastic behavior.6 Radiotherapy: Primary external beam ra- Flow cytometric analysis, by assessing diotherapy has been used for treatment of DNA content ofneoplastic cells, has helped muscle invasive disease with satisfactory re- to predict tumor behavior. Tumor cells that sults in selected patients. Long-term surviv- express an aneuploid chromosomal num- al, however, is far from that achieved by ber are found to exhibit aggressive behav- radical surgery in equivalent patients.4 Ra- ior.6 Cytogenic analysis has also revealed diotherapy can be used in patients who re- marker chromosomes that appear to be fuse or would not tolerate radical surgery. predictive of cellular behavior.6 Radiotherapy has been used preoperatively Our investigation has led to the develop- in the past, but critical analysis has revealed ment of antibodies to unique antigens ex- no survival advantage as compared with pressed on neoplastic urothelial cells, which radical surgery alone. have been shown in extensive evaluation to have significant predictive value regarding Metastatic disease. Metastatic transitional tumor behavior and prognosis.'1920 Work is cell carcinoma has an ominous prognosis with currently under way to develop therapeutic only a 10% to 15%/ -year survival rate. Mul- and diagnostic methods with these highly tiagent chemotherapy for the treatment of selective monoclonal antibodies.

1476 Canadian Family Physician VOL 37: June 1991 Conclusion photodynamic therapy. J Urol WENTIODJSK@ Significant advances in the field of 1985; 134:675-8. 9. Torti FM, Lum L. The biology and treat- salbutamol (as sulphate) bladder cancer have thus opened new ment of superficial bladder cancer. J Clin avenues for both diagnosis and thera- Oncol 1984;2:505-3 1. Delivery you py. Recognition of the natural history 10. Morales A, Eidinger D, Bruce AW. Intra- and heterogeneity of bladder cancer cavitary bacillus Calmette-Guerin in the can count on. provides a more logical approach to treatment of superficial bladder tumors. J Urol 1976;1 16(10):180-3. IN VENTODISK- DISKHALER- its management. Bacille Cal- 11. Sarosdy MF, Lamm DL. Long term re- salbutamol (as sulphate powder for Inhalation) ACTION: Bronchodilation through stimulation of mette-Guerin immunotherapy has sults of intravesical bacillus Cal- beta-2-adrenergic receptors in bronchial smooth muscle, been a significant advance, allowing mette-Guerin therapy for superficial thereby causing relaxation of muscle fibres. bladder cancer. 7 Urol 1989; 142(3): 719-22. INDICATIONS: Symptomatic relief of bronchospasm due to bladder preservation in many pa- bronchial asthma, chronic bronchitis and other chronic bron- tients who would have re- 12. Orihuela E, Herr HW, Pinsky CM, chopulmonary disorders in which bronchospasm is a compli- previously WVhitmore WFJr. Toxicity of intravesical cating factor. quired radical cystectomy for disease BCG and its management in patients with CONTRAINDICATIONS: Hypersensitivity to any of the ingre- control. dients and tachyarrhythmias. The development of conti- superficial bladder tumors. Cancer WARNINGS: The safety of salbutamol in pregnancy has not nent urinary diversions and function- 1987;60:326-33. been established. 13. Studer UE, Ackermann D, Casanova Care should be taken with patients suffering from myocar- al bladder replacements has made dial insufficiency, arrhythmia, hypertension, diabetes mellitus radical cystectomy more acceptable GA, Zingg EJ. A newer form of bladder or thyrotoxicosis. substitute based on historical perspectives. Occasional patients have been reported to have developed to both patients and their physicians. Semin Urol 1988;VI:57-65. severe paradoxical airway resistance with repeated excessive use of sympathomimetic inhalation preparations. The cause Successful management of metastatic 14. Lieskovsky G, Boyd SD, Sidnner DG. of this refractory state is unknown. It is advisable that in such disease remains elusive, although Management of late complications of the instances the use of the preparation be discontinued im- Kock pouch form of urinary diversion. mediately and altemate therapy instituted, since in the reported multiagent chemotherapy now pro- 7 cases the patients did not respond to other forms of therapy EUrol 1987;137:1 146-50. until the drug was withdrawn. Fatalities have been reported vides a potentially successful ap- 15. Ahlering TE, WVeinberg AC, Razor B. A following excessive use of aerosol preparations containing sympathomimetic amines, the exact cause of which is proach for these patients. The use of comparative study of the ileal conduit, unknown. Cardiac arrest was noted in several instances. chemotherapy in conjunction with Kock pouch and modified Indiana pouch. PRECAUTIONS: 1. Use with caution in patients sensitive to J Urol 1989;142:1193-6. sympathomimetic amines. Other beta-adrenergic drugs, e.g., radical surgery may lead to improved isoprenaline, should not be given concomitantly 2. Not recom- survival in patients with invasive blad- 16. Sternberg CN, Yagoda A, Scher HI, et mended for children under 6 years. 3. To ensure the proper al. M-VAC (methotrexate, vinblastine, dox- dosage administration of the drug, the patient should be der cancer. U instructed by a physician or other health professional in the use orubicin and cisplatin) for advanced transi- of the Diskhaler. * - - 0 * 0 0 * - - - - 0 0 - - 0 -0 * - 0 - - 0 0 0 0 0 0 - 0 - 0 - tional cell carcinioma of the urothelium. J ADVERSE REACTIONS: Although serious adverse effects are reprints to: Dr Yves Urol 1988; 139:461-9. uncommon in association with the recommended doses, in- Requestsfor creased heart rate, peripheral vasodilation, headache, dizzi- Fradet, Laval University Cancer Research 17. Sternberg CN, Yagoda A, Scher HI, et ness, nausea, tremor, and palpitations may occur. Centre, L'Hdtel-Dieu de Quebec, 11 coti du al. Patterns of response, survival and re- SYMPTOMS AND TREATMENT OF OVERDOSE: Overdosage lapse in advanced urothelial cancer follow- may cause tachysardia, cardiac arrhythmia, hypertension and Palais, Quibec, QC GIR 275 in extreme cases, sudden death. In order to antagonize the ing M-VAC therapy [abstract]. Proc Am Soc effect of salbutamol, the use of a beta-adrenergic blocking References Clin Oncol 1989;8:129. agent, preferably one of the relatively cardioselective ones (e.g. 18. HI. metoprolol, atenolol), may be considered. 1. Silverberg E, Boring CC, Squires TS. Scher Chemotherapy for invasive DOSAGE AND ADMINISTRATION: Cancer statistics, 1990. CA 1990;40:9-26. bladder cancer: neoadjuvant versus adju- Adults: 200 or 400 mcg before exertion, or to relieve acute vant. Semin Oncol 1990; 17:555-65. bronchospasm. For chronic maintenance or prophylactic 2. Raghavan D, Shipley MU, Gamick MB, therapy, 200 mcg or 400 mcg, 3 to 4 times daily. Maximum Russell PJ, Richie IP. Biology and manage- 19. Fradet Y, Tardif M, Bourget L, RobertJ, 1600 mcg per day. ment of bladder cancer. N Eng1 J Med Laval University Urology Group. Clinical Children (6 years or older): 200 mcg before exertion, or to cancer progression in urinary bladder tu- relieve acute bronchospasm. For chronic maintenance or pro- 1990;332:1 129-38. phylactic therapy 200 mcg, 3 to 4 times daily. Maximum 800 3. Thompson IM, Peek M, Rodriguez FR. mors evaluated by multiparameter flow cy- mcg per day. The impact of cigarette smoking on stage, tometry with monoclonal antibodies. Cancer AVAILABIUTY: Ventodisk Blisters contain a mixture of micro- Res 1990;50:432-7. fine salbutamol sulphate and larger particle lactose. Each pale grade and number of recurrences of transi- blue double-foil disk contains 8 sealed blisters with a mixture tional cell carcinoma of the bladder. J Urol 20. Fradet Y, Islam N, Boucher L, Par- of 200 mcg of microfine salbutamol (as sulphate) with lactose. 1987;137:401-4. ent-Vaugeois C, Tardif M. Polymorphic ex- Each dark blue double-foil disk contains 8 sealed blisters with a mixture of 400 mcg microfine salbutamol (as sulphate) with 4. Kantoff PWV. Bladder cancer. Curr Probl pression of a human superficial bladder lactose. Cancer 1990;XIV:235-9 1. tumor antigen defined by mouse monoclo- The contents of each blister are inhaled using a device called 5. Heney NM, Ahmed S, Flanagan 1IJ, et nal antibodies. Proc NAatl Acad Sci U S A the Diskhaler which pierces through the blister and releases al. Superficial bladder cancer: progression 1987;84:7227-3 1. the drug when the patient inhales, by breath actuation. REFERENCES: 1. Hargreave, FE., Dolovich, J. and Newhouse, and recurrence. 7 Urol 1983; 130:1083-6. MT Editors, The assessment and treatment of asthma: 6. Fradet Y. Biological markers of prognosis A conference report, J Allerg Clin Immunol, Vol. 85, No. 6, June 1990. in invasive bladder cancer. Semin Oncol Product Monograph Available on Request to Physicians and 1990; 17:533-43. Pharmacists. 7. Prout GR, Lin C-WV, Benson R, et al. ® Registered Tradmark, Glaxo Canada Inc. Photodynamic therapy with hematoporphyrin derivative in the treatment of superficial transitional-cell carcinoma of the bladder. .A Eng1J Med 1987;317(20):1251-5. ms_] Glaxo Canada Inc. 8. Benson RC Jr. Treatment of diffuse transitional cell carcinloma in situ by wholc bladder hematoporphyrin derivative

Canadian Family Physician VOL 37 june 1991 1477