REVIEW ARTICLE
CURRENT PERSPECTIVES ON DIAGNOSIS AND TREATMENT OF SUPERFICIAL BLADDER CANCER DONALD L. LAMM, M.D. GREG GRIFFITH, M.D. LOREEN L. PETTIT, M.D. UNYIME 0. NSEYO, M.D.
From the Department of Urology, Health Science Center, West Virginia University, Morgantown, West Virginia
An estimated 500,000 persons in the United States are living with bladder cancer, making it the fourth most prevalent noncutaneous malignancy. Three fourths of patients present with superficial disease which is amenable to complete surgical resection. However, disease will recur in more than 75 percent of these patients following resection. Although improvements in diagnosis and treatment account for much of the increase in prevalence of bladder cancer, the number of new cases continues to rise each year. In 1991 an estimated 50,200 persons were diagnosed with bladder cancer and 9.500 died of the disease. ’The most frequent age of onset is in the mid sixties, and men are affected three times as often as women. Transitional cell carcinoma accounts for over 90 percent of bladder malignancies. followed by squamous cell carcinoma (5 % ), adenocarcinoma ( < 2 % ) ~ and rhabdomyosarcoma (< 1% ) . Etiology Bladdler cancer was one of the first malignancies shown to result from exposure to chemical Beta-naphthylamine, previously carcinogens. associated with aniline dyes and used as an antioxidant in the rubber industry, is one of several potent bladder carcinogens which have been identified and consequently largely removed from the modern workplace. Epidemiologic studies, however, show continued increased risk in a wide variety of occupations having exposure to such substances as gasoline, paints, oils, chromium, and zinc.2 Though industrial carcinogerrs are important, a much greater number of people are exposed to the known bladder carcinogen, tobacco. It has been estimated that
over one half of the bladder cancer cases in men and one quarter to one third of the cases in women result from cigarette smoking. Evidence suggests that smokeless tobacco is also a bladder carcinogen. Additional risks for bladder cancer include chronic infection and inflammation, phenacetin abuse, cyclophosphamide, and pelvic irradiation. Even increased water consumption in some areas of the world has been associated with an increased risk of bladder cancer, an observation which points out the futility of attempts to completely eliminate all risk factors for cancer. While viral oncogenes have been identified in transitional cell carcinoma as well as several other cancers, such material is thought to be an intrinsic component of the vertebrate genome. Though viral oncogenes are apparently an integral part of the process of malignant transformation, there is no evidence that viral infection per se results in bladder cancer. Clinical Features Eighty percent or more of patients with bladder cancer present with hematuria. Intermittent gross total painless hematuria is typical, and microscopic hematuria is common. The intermittent nature of bleeding should be stressed, since patients and physicians alike can be mistakenly reassured when hematuria resolves. The patient who presents with advanced disease and a history of a previous episode of hematuria which was not fully evaluated is a tragedy which is repeated much too often. Symptoms of bladder irritability such as urinary frequency, urgency, and dysuria occur
in as many as one third of patients. Such symptoms mimic cystitis and prostatitis. Tumors of higher grade, including carcinoma in situ, have an increased propensity to cause such irritative symptoms. Fortunately, higher grade tumors, especially carcinoma in situ, are more likely to have a diagnostic urinary cytology. Urinary cytology, therefore, is a useful screen for bladder cancer in these patients. Symptoms of advanced disease including weight loss, abdominal mass, suprapubic or flank pain, and lymphedema are uncommonly seen today. Diagnosis Cystoscopic examination of the bladder continues to be the primary diagnostic tool since urinary cytology and imaging studies have high false-negative rates. Flexible cystoscopy can be accomplished without anesthesia in almost any patient, but rigid cystoscopy provides a clearer view of the bladder. It is axiomatic that the entire surface of the bladder should be carefully and closely. viewed, and a 120-degree lens should be used if the anterior bladder neck is not visualized with the right-angle lens. A high degree of suspicion is appropriate, and biopsies of raised, roughened, or reddened areas are best done with cupped forceps. Often one or two biopsies can be done without anesthesia, but patients with a high risk for bladder cancer are best examined and biopsy done under anesthesia so that completeness is not compromised by concern for patient discomfort. Bimanual examination under anesthesia is also an integral part of clinical staging, and sometimes even small superficial-appearing tumors can be associated with an unsuspected, nonvisualized, but palpable mass. Even careful and expert cystoscopic examination may fail to diagnose bladder cancer, as carcinoma in situ may be entirely normal in appearance. Most bladder tumors are more red in color than surrounding urothelium and can be seen from a distance. Tumors that are exactly the same shade as the rest of the bladder can be easily missed unless the bladder wall is inspected from close distance (within a few centimeters). Fortunately, urinary cytology is almost invariably positive in patients with carcinoma in situ since tumor cells are poorly differentiated, and have defective intercellular adherence and readily slough off. Indeed, in some cases the diagnosis of carcinoma in situ is more easily made with urinary cytology than bladder
biopsy, since biopsy specimen may show, only the denuded, inflamed bladder wall.‘~ Methylene blue has been used to stain transitional cell carcinoma and facilitate visualization and selection of biopsy sites. This technique is most useful in patients who have a positive cytology and no visible tumor. A solution of 0.2% methylene blue is placed in the bladder for ten minutes prior to cystoscopy. Transitional cell carcinoma and area of inflammation can be identified by blue staining. Random bladder biopsy specimens are useful in the management of bladder cancer. Biopsy specimens are taken of the margins of tumors, visibly suspicious areas, normal-appearing urothelium at multiple preselected sites such as the lateral walls, dome, posterior wall, trigone, and bladder neck, and, importantly, the prostatic urethra. Atypia or carcinoma in situ are poor prognostic signs,4 and up to 40 percent of patients undergoing cystoprostatectomy are found to have transitional cell carcinoma in the prostatic urethra. 5 The latter is of particular importance with the advent of orthotopic bladder substitution procedures where recurrence of tumor in the urethra can be devastating. In addition to urinary cytolo&T, which is highly variable in accuracy at different institutions, some have used flow cytometry, quantitative fluorescence image analysis (QFIA), rnonoclonal antibody immunocytolob3/, cluantitation of nuclear roundness and nuclearlcytoplasmic ratio, and fibrin degradation product (FDP) analysis to aid the diagnosis of bladder cancer. In our experience, FDP is more accurate than flow or QFIA. Recently immunocytology has been reported to have a 90 percent sensitivity compared with 70 percent for standard cytology and less than 50 percent for flow cvtometry.” Currently, however, these additional diagnostic techniques are generally considered investigational, and their place in routine clinical management remains to be defined. Intravenous urography (IVP) rernains the mainstay of radiographic evaluation in bladder cancer. The IVP provides efficient visualization of the upper urinary tract and is useful in the differential diagnosis of hematuria. While upper urinary tract tumors occur in only 2 to 3 percent of patients with bladder cancer,7 oarcinema in situ occurs more frequently and a baseline IVP or retrograde pyelogram is needed to demonstrate upper urinary tract anatomy. For superficial tumors not invading the detrusor muscle, additional imaging studies such as
T. (0)
T, (4
T
T,,
T,,
CC)
(6)
Mucosa Submucosa
Metastases M (0)
N-
(D. CD,
of Jewett-Strong bladder cancer staging .s!pF’I(:uHt~:1. Mar.shall:s modification tvm. Adapted from Skinner DC: Current state of classification and staging of hladdcr cancer. Cancer Res 37: 2838 (1977).
cystoglram, pelvic computed tomography, magnetic resonance imaging, ultrasonography, and bone scans are not necessary and not cost effecti\,e. Surgery Excisional transurethral biopsy (resection) is diagnostic, therapeutic, and essential for accurate staging. Transurethral surgery requires extensive experience and endoscopic training as well as considerable manual dexterity. Resection is preferably started in relatively safe areas, avoiding the dome and lateral walls overlying the obturator nerve until all other tumors have been removed so that the procedure can be terminated quickly if bladder perforation occurs. Excessive cautery current should be avoided to prevent charring of the specimen, but sufficient current should be used to permit smooth, easy cutting. Muscle should be included in the specimen to permit accurate staging, and care is taken to avoid distention of the bladder so that these specimens can be taken without bladder perforation. Areas of carcinoma in situ are fulgurated, and the roller electrode is used to fulgurate the tumor base and margins of resection. After resection of all visible tumors, the ‘IO-degree lens is reinserted to confirm that resection is complete. Pathologic Examination
and Staging
Pathologic review should provide information important to clinical management (Figs. 1
and 2). Both grade and stage correlate with prognosis. Grade I tumors rarely progress to muscle invasion; only 2 percent of grade I Stage Ta tumors and 7 percent of grade I Stage Tl tumors progress. By contrast, progression of grade III tumors is common: 25 percent for grade III Stage Ta and 48 percent for grade III Stage Tl. Thirty percent of tumors with lamina propria invasion, Stage Tl, will progress in less than four years. 4 If muscle invasion is present, aggressive treatment rather than intravesical therapy is required. Stage T2 tumors, invading less than half way through the cletru$,or muscle: Stage T3a tumors, invading into the $,econd half of detrusor muscle; and Stage T3b tllmora. extending into perivesical fat, should (in our opinion) preferably be treated with radical c!-stectomy. Indications
for Intravesical
Therapy
Not all patients with superficial bladder cancer require intravesical therapy. Patients with a solitary low-grade Stage Ta tumor are at low risk of recurrence and progression and can be TARI.E I. _-___
Indications
for intraoc&cal
Multiple primary tumors Multiple tumor recurrences (:rade III tumor Stage Tl tumor Positive cvtolo53
therapy
Carcinoma
-------
in situ
Papillary tumors without invasion Invasion of lamrna propria
-------
__c--t__-.
Superficial muscle invasion Deep muscle invasion ------Invasion of perivesicular fat __-_----Invasion of prostate, vagina Fixed pelvic
B
C
uterus
to or abdominal
Pelvic
wall
A
A
I
_I-
nodes
Distant
metastases
Nodes above aortic bifurcation
FIGURE2. Comparbons of American and TNM staging systems for bladder cancer. Adapted from Skinner DG: Current state of classification and staging of bladder cancer, Cancer Res 37: 2838 (1977).
spared the expense and morbidity of intravesical therapy as well. Clear indications for intravesical therapy include multiple primary tumors, tumor recurrence, grade III tumor, Stage Tl tumor, positive post-resection urinary cytology, and dysplasia or carcinoma in situ (CIS) on random biopsy specimen (Table I). The goals of intravesical therapy are the prevention or postponement of tumor recurrence, eradication of residual unresectable papillary transitional cell carcinoma or carcinoma in situ, prevention of tumor progression, reduction of the need for radical cystectomy, and maintenance and prolongation of good quality life. While prevention of tumor recurrence is a significant achievement, prevention of tumor progression is by far the most important goal. Intravesical
Chemotherapy
Effective intravesical chemotherapy dates back to 1955 when thiotepa was first instilled in
304
the bladder to treat superficial bladder cancer.* Since that time controlled studies have demonstrated that four commonly used intravesical cytotoxic chemotherapies are effective in the treatment of residual tumor and the prevention of tumor recurrence. These intravesical chemotherapies are: thiotepa, doxorubicin (Adriamycin), mitomycin C (Mutamycin), and ethoglucid (Epodyl). (Ethoglucid is not commercially available in the U.S.) Published response rates in 1,582 patients with residual papillary transitional cell carcinoma show average complete response rates of 29 percent for thiotepa, 38 percent for doxorubicin, 47 percent for mitomycin C, and 55 percent for ethoglucid.g While these data suggest that ethoglucid and mitomycin may be more effective than thiotepa, prospective controlled studies have failed to confirm the superiority of newer chemotherapies over thiotepa. Nineteen randomized, controlled, prospective studies have compared intravesical chemotherapy
with surgery alone. B I9 Six of 10 thiotepa studies showed a statistically significant advantage for intravesical thiotepa, and reduction in tumor recurrence averaged 17 percent. Two of four doxorubicin studies and two of five mitomycin studies ‘were statistically significant, with relative advantages of tumor recurrence of 18 percent and 16 percent, respectively. Multiple studies comparing one intravesical chemotherapy with another have failed to confirm that any of the newer chemotherapies are significantlv better. Extensive data now confirm that intravesical chemotherapy reduces the rate of short-term tumor recurrence by a modest 16 percent to 18 percent. Unfortunately, the long-term rate of tumor recurrence and, more importantly, the rate of disease progression are not reduced. With over 3,000 patients enrolled in controlled studies,g 2o evidence fails to supplort the conclusion that intravesical chemotherapy reduces the rate of tumor progression. One approach to improve the benefits of intravesical chemotherpay has been to keep patients on maintenance regimens. Recently, reports by, Flammzl and Huland et dz2 demonstrate that maintenance doxorubicin or mitomycin offer no benefit over shorter courses. Indeed. evidence suggests that very early shortcourse lchemotherapy may provide the highest relative benefit.23 With thiotepa, the two studies showing the greatest advantage, and indeed the only study to show a statistically significant advantage of chemotherapy at the p < 0.001 level, used early postoperative thiotepa. 13.23 Studies with thiotepa also suggest that the patients who benefit most from intravesical chemotherapy are those with low-grade tumors.“’ Intravesical
Immunotherapy
It is a mistake to group chemotherapy with immunotherapy since the mechanisms of action, th,e principles of treatment, and the potential benefits of therapy are distinctly different. The commonly used intravesical chemotherapies, with the exception of the intercalating agent doxorubicin, are alkylating agents, and all have a similar mechanism of action. Immunotherapy, as exemplified by the first effective immunologic treatment for bladder cancer, bacillus Calmette-Guerin (BCG), stimulates immune defenses. While cytotoxic chemotherapy is effective only against existing malignancy, immunotherapy has the potential to induce specific immunity to tumor, making pos-
sible the prevention of tumors that have not yet developed. Two immunotherapies are commercially available in the United States: BCG and alpha-interferon, BCG
immunotherapy
Following the demonstration in the early 1970s that BCG could cause regression of cutaneous malignancies, a number of investigators independently evaluated BCG irnmunotherapy in bladder cancer. Morales, Eidinger, and Bruce24 were the first to report clinical success in 1976, when they observed a l%fold reduction in tumor recurrence in patients given a sixweek course of intravesical and percutaneous BCG. BCG immunotherapy has subsequently been confirmed by investigators around the world to be highly effective in the reduction of tumor recurrence, the treatment of residual papillary transitional cell carcinoma, and, most importantly, the treatment of carcinoma in situ. Response rates in the treatment of residual papillary disease average 55 percent.“” In the treatment of carcinoma in situ, with 663 patients treated in fifteen studies,“’ x the average complete response rate is ‘73 percent. higher than that achieved with any other intravesical agent. In the prevention of tumor recurrence. the relative benefit of BCC is 4Fj percent in 456 patients. and four of five controlled studies are statistically significant (p < 0.001) .rfi 27 3o Direct prospective randomized comparisons of BCG with intravesical chemotherapy have found it to be significantly superior to thiotepa, doxorubicin, and mitomycin in the prevention of tumor recurrence.31 33 When intravesical chemotherapy is used prophylactically, tumor recurrence is delayed, but after five years the percentage of patients who have recurrence is not decreased.“” With BCG immunotherapy, however, benefits appear to be long-term. For example, in the Southwest Oncology Group study comparing BCG with doxorubicin in patients with rapidly recurring transitional cell carcinoma, only 17 percent of patients were estimated (Kaplan-Meier) to be tumor-free at five years compared with 37 percent of BCG-treated patients. In patients with carcinoma in situ, the difference was even more pronounced, 18 percent versus 45 percent (p < 0*0001).:~~ Tfimor progression
While chemotherapy has failed to reduce tumor progression, evidence suggests that immunotherapy with BCG does in fact reduce
tumor progression. Experience with 90 nonranhas shown that the domized patients progression to muscle invasion can be reduced from 8 percent in controls to 3 percent with BCG therapy., ‘I4 This difference is not statistically significant, but the reduction in invasion of lamina propria from 23 percent to 6 percent was significant. In randomized studies, Herr et al. 36 observed a delay and reduction in muscle invasion from 35 percent in controls to 28 percent with BCG treatment (p < O.Ol), and Pagano et a1.3”observed a reduction from 17 percent to 4 percent (p < 0.001). The need for cystectomy was also significantly reduced in Herr’s study, and despite the more frequent and earlier use of cystectomy, mortality was significantly reduced in the BCG group from 32 percent to 14 percent.“5
BCG complications While 95 percent of patients tolerate BCG without significant toxicity, serious and even fatal reactions can occur. Septic reactions, characterized by fever, hypotension, disseminated intravascular coagulopathy, and multi-organ failure have been temporally associated with BCG administration. Such reactions are typically associated with traumatic catheterization or intravenous absorption of BCG.37 Recent evidence suggests that hypersensitivity is a significant component of this toxicity, and current recommendations for treatment are isoniazid (330 mg), rifampin (600 mg), and prednisolone (40 mg) daily.38
Alpha-interferon The remarkable efficacy of immunotherapy with BCG has pointed out the general potential of immunotherapy in the treatment of superficial bladder cancer and raises an obvious question: can alternative immunotherapies produce the benefits of BCG without the toxicity? Several immunotherapeutic agents are currently being evaluated around the world. However, the only commercially available immunotherapeutic alternative to BCG in the United States is alpha-interferon. Considerable evidence has now accumulated to indicate that recombinant human interferon alpha-2b has activity in the treatment of transitional cell carcinoma. In a phase I-II trial, Torti et aZ.3y evaluated interferon alpha-2b in heavily pretreated patients with papillary and in situ transitional cell carcinoma. In patients with papillary transitional cell carcinoma, complete response was observed in 4 of 16 pa-
tients, 3 of whom had previously failed to respond to intravesical chemotherapy. As expected with immunotherapeutic agents, response in carcinoma in situ (CIS) was higher. Nine of 19 CIS patients (47 % ) had complete response to interferon, though 3 of these patients had subsequent grade I papillary transitional cell carcinoma. Patients with prior chemotherapy had a complete response rate in CIS which was not significantly different from those who had not had prior chemotherapy. Dosage of interferon alpha-2b in this study ranged from 50 to 1,000 million units given weekly for eight weeks. Complete responses at the lower doses (50 to 100 million units) occurred as frequently as responses at doses of 400 to 1,000 million units, confirming that high immunotherapeutic dose does not necessarily correlate with high therapeutic activity. Five of 10 patients with complete response remained disease free at 18 + to 37 + months. Importantly, no serious toxicity was observed in this study. No patient had hematuria, dysuria, or myelosuppression, and only 15 of 55 patients (27%) had mild flu-like symptoms. The maximum tolerated dose was not reached at 1,000 million units. In a subsequent phase III trial, Glashan40 randomized 87 patients with biopsy-proved carcinoma in situ to receive 10 or 100 million units of interferon alpha-2b weekly for twelve weeks followed by monthly instillations to one year. Eighty-five patients were subsequently evaluable for tolerability and 80 for drug activity. Patients could have received a variety of surgical and intravesical therapies prior to entry into this trial. Two of 37 evaluable patients (5 %) receiving low-dose interferon alpha-2b had complete response, while 20 of 43 evaluable patients (47%) receiving high-dose interferon alpha-2b had complete response (p < 0.0001). In the low-dose group, an additional 12 of 37 patients (32%) had evidence of complete resolution of carcinoma in situ on rebiopsy, but had residual positive findings on urinary cytologic examination. In the high-dose group, an additional 9 patients had complete response by biopsy, but not by cytology. It is notable that 6 of 9 patients previously treated with BCG showed objective responses to interferon, including 2 patients who achieved complete responses to high-dose therapy. In the low-dose group, disease progression was observed in 14 of 37 patients (38 %) compared with only 6 of 43 in the high-dose group (14 %). The duration of
has now ranged from six nlontlls to ov(‘r f\vo J’ears. S!sterrlic absorption of interferon alpha-2h in this stud!. was not observed. As in the earlier studv b;; X)rti rat al. .‘I’no local toxicit), oc~curred and flu.-like s>,rnptoms were uncommon. found in onl!. ;S percent of the low-dose and I7 percent of the high-dose subjects. There were no cases of patients discontinuing treatment as a consecltlellce of arl\rerse reactions to interferon alpha211.
co~rrplei~~ rtyxmsc’s
Xlternative
Treatments
Several in\.estigators have demonstrated the efficaq of photodynamic therapy (PDT) in ablating papillaq~ transitional cell carcinoma (‘XC) and carcinoma in situ of the urinaq bladder. and in preventing recurrence in patients \vlro halve failed conventional intravesical therap!, for superficial transitional cell carcilloma. A single treatment with PDT has been rcJporte,d to eradicate papillary TCC in ‘70 to 9S percent of l’atients. 4’However, complete tumor ablation N.;~s generally limited to patients who had tumors that were less than 2 cm in diameter. Response rates of 80 to 100 percent are reported in patients with refractory CIS treated with I’1YI’.2’ With a mean follow-up of 19.4 months (range 6 to 50 months), we have obser\:ed tumor recurrence in 2 of 11 patients (1X “%) with recurrent TCC treated prophylacticall\. with l’I?T I . ,1.X Kqholc~
lil,ipct
iwnocyanin
C;on~;iderat:,le laboratory and clinical evdence now suggests that the highly antigenic respirai.r)r!. pigment (hemolymph) of the mollust Mqathrlria crenulata has significant antitumor acti\GtJ: Studies in Europe have suggested that intravesical and percutaneous kq.hole linlpet hemocyanin (KLH) results in bladder tumor recurrence rates which are lower than those observed with mitomycin and equal to those:, obser\red with ethoglucid.44 4r, Other
I wm rtrdogicdl~~
active agvn ts
Originally termed T-cell growth factor, interlcukin !Z(II,-2) is produced by helper T lymphoc!,tes al Id serves to stimulate lymphocyte proliferatioir . IIltralesional IL-2 was reported b> Pizza ~1 nl:+” l-0 result in complete tumor regression in 3 of 6 patients receiving 4,000 units of II ,-2. HIlland”’ has similarly observed complete rqxm:;? in 1 of 4 patients given continuous in-
fusion intravesical IL-2, clearl!, suggesting activity of IL-2 in bladder cancer. Other agents with a suggestion of irnmrmologic activity in bladder cancer include maltose tetrapalmitate OK-432. a lyol)hilized attcanuated streptococcus vaccine. and the interferon inducers polyI:C and bropirimine. Conclusions Intravesical chemotherapy results in tumor regression in one quarter to one half of patients with papillary and in situ transitional cell carcinoma of the bladder. Used prophylactically, chemotherapy reduces short-term tumor recurrence by 16 percent to 18 percent, but does not appear to reduce long-term recurrence. disease progression, or mortality. Efforts are Ilnderwa) to improve intravesical chemotherapy, and multiple approaches not available to systemic chemotherapy are possible. Immunotherapy, as exemplified 1~~7 BCG. has a mechanism of action which is different from classic cytotoxic chemotherapy. B(:G treatment results in regression of 50 percent to 80 percent of papillary and in situ carcinomas. and reduces tumor recurrence by as much as 50 percent. The benefits of BCG immunotherapy appear to be long-term in some patients, and controlled studies suggest that tumor progression and even mortality can be reduced. Enthllsiasm for widespread use of BCG is. however, tempered by concerns regarding significant toxicity. Alternative immunotherapies have the prospect of being highly effective as well as less toxic. Although few alternative immunotherapies are commercially available in the U.S. at this time, research is underway to develop these agents. Interferon alpha-2b is one agent Jxhich has demonstrated anti-tumor activity in papillary (25 % complete response) and in situ (4’i % complete response) carcinoma. Further research, and possibly the use of combination immunotherapies, should significantly improve treatment options in the hlture. Health
Science Center. Koom 2237 West Virginia lJniversit\, Morgantown, West Virginia 26506 (DR. LAMM)
4. Heney NM, et al: Superficial bladder cancer: progression and recurrence, J Urol 130: 1083 (1983). 5. Wood DP, Montie JE, Vandcrburg-Medendorp S, and Lcvin HS: Transitional cell carcinoma of the prostate in cystoprostatectomy specimens removed for bladder cancer. J Urol 141: 346 (1989). 6. Klan R, Huland E, Baisch H, and Huland ff: Sensitivity of urinary quantitative immunocytology with monoclonal antibody 486 P3112 in 241 umelected patients with bladder carcinoma. J Urol 145: 495 (1991). 7. hlalkowicz SB, and Skinner IX:: Dcvclopmcnt of upper tract carcinoma after cystrctomy for bladder carcinoma. Urolog! 36: 20 (1990). 8. Bateman JC: Chemotherapy of solid tumors with trimethylene triphosphoramide, N Engl J Med 252: 879 (1955). 9. Kowalkowski TS, and Lamm DL: Intravesical therapy of superficial bladder cancer, in Resnick M (Ed): Current Trends in Urology, Baltimore, Williams and Wilkins, 1989. 10. Prout GR, et al: Long-term fate of 90 patients with supcrficial bladder cancer randomly assigned to rcccive or not receive thiotepa, J Urol 130: 667 (1983). 11. Medical Research Council: The effect of intravesical thiotepa on the recurrence rate of newly diagnosed superficial bladder cancer, Br J Urol 57: 680 (1985). 12. Niijima T, Akaza H. Koisok K, and the Japanese Urologic Cancer Research Group for Adriamycin: Randomized clinical trial on chemoprophylaxis of recurrence in cases of superficial bladder cancer, Cancer Chemother Pharmacol (Suppl) 2: 579 (1983). 13. Zincke H, et al: Influence of thiotepa and doxorubicin instillation at time of transurethral surgical treatment of bladder cancer on tumor recurrence: a prospective, randomized. double blind, controlled trial, J Urol 129: 505 (1983). chemotherapy of superficial 14. Kurth KH, et al: Adjuvant transitional bladder carcinoma: preliminary results of a European Organization for Research on Treatment of Cancer randomized trial comparing doxoruhicin hydrochloride, ethoglucid and transurethral resection alone, J Urol 132: 258 (1984). 15. Rubben H, et al: Natural history and treatment of low and high risk superficial bladder tumors, J Ural 139: 283 (1988). randomized study of aclju16. Ruhhen II, et al: Prospective vant therapy after complete resection of superficial bladder cancer: mitomycin C versus BCG Connaught versus TUR alone, in deKernion JB (Ed): International Society of Urology Reports, New York, Churchill Livingstone, 1990, chap 3. 17. Huland H, and Otto U: Mitomycin instillation to prevent recurrence of superficial bladder carcinoma, Eur Urol 9: 84 (1983). 18. Kim HH, and Lee C: lntravesical mitomycin C instillation as a prophylactic treatment of superficial hladder tumor (abstr.), J Urol 139: 245A (1988). 19. Tolly DA, et al: Effect of intravesical mitomycin C on rccurrence of newly diagnosed superficial bladder cancer: an interim report from the Medical Research Council subgroup on SIIperficial bladder cancer, Br Med J 296: 1759 (1988). 20. Newling D: Intravesical therapy in the management of ~(1. perficial transitional cell carcinoma of the bladder: the experirncc of the EORTC GU group, Br J Cancer 61: 497 (1990). 21. Flamm J: Long-term versus short-term doxorubicin hydrochloride instillation after transurethral rcycction of superficial bladder cancer, Eur Urol 17: 119 (1990). 22. Huland H, ~1 al: Comparison of different schcdulrs of cytostatic intravesical instillations in patients with superficial bladder carcinoma: final evaluation of a prospective multicentcr stud) with 419 patients, J Urol 144: 68 (1990). 23. Burnand Kc:. cat ~1: Single-dose intravcsaical thiotcpa as an adjuvant to cystodiathcrm!in the treatment of transitional ccl1 bladder carcinoma. Br J Ural 48: 55 (1976). 24. Morales A, Eidinger D, and Bruce A\V: Intracavitary bacillus Calmette-G&in in the treatment of superficial hladdcr tumars, J Ural 116: 180 (1976).
308
25. Sosnowski JT. and Lanrm DL: Immunotherapy of bladder carcinoma. in Crawford ED, and Das S (Eds): Current Cenitourinary Cancer Surgery. Philadelphia, Lea and Febiger, 1990, chap 47. 1’480. 26, I,amm DL: Rc.sulth of clinical trials of B(:G thchrap): AU.4 X,da> 4: 22 (1991). 27. Lamm DL: Bacillus Calmette-Gu&in immunotherapy for bladder cancer, J Urol 134: 40 (1985). 28. Herr HW, ct (I/: Long-term effect of intravesical bacillus Calmettc-Guerin on flat carcinoma in situ of the bladder, J Urol 134: 40 (198.5). 29. Paaano E: ct al: Long-term effect of intravcsical bacillus Calmctte-G&in regime in superficial bladder cancer therapy: is it effective?, J Urol 146: 32 (1991). 30. Herr IIW, rt (11: Experience with intravesical bacillus Calmette-Gukrin therapy of superficial bladder tumors, Urology 25: 119 (1985). 31. Fauhiainen K, Rintala E, and Alfthan 0: Immunotherap) (BCG) versus chemotherapy (MMC) in intravesical treatment of superficial urinary bladder cancer, in DeKcrnion JB (Ed): International Society of Urolok~ Reports, New York, Churchill Livingstonc, 1990, chap 2, 1’ 13. 32. Martinez-Pirieiro JA, et al: Bacillus Calmette-Gukrin versus doxoruhicin versus thiotepa: a randomized prospective stud) in 202 patients with superficial bladder cancer. J Urn1 143: 502 (1990). trial of intravcsical dox33. Lamm DL, et al: A randomized orubicin and immunotherapy with bacillus Calmette-G&in for transitional cell carcinoma of the bladder, N Engl J Med 325: 1205 (1991). .34. Reynolds R, Stogdill UD, and Lamm DL: Disease progression in BCG-treated patients with transitional cell carcinoma of the bladder (ahstr), J Urol 133: 211A (1985). 3s. Iferr W, ct al: Bacillus Calmette-G&in therapy alters the progression of superficial bladder cancer, J Clin Oncol 6: 1450 (1988). 36. Pagano F, et al: A low-dose bacillus Calmette-G&in regimen in superficial bladder cancer therapy: is it effcctivc?, J U& 146: 32 (1991). .37. Rawls iv, pt al: Fatal sepsis following intravesical bacillus Calmette-G&in administration for bladder cancer, J Urn1 144: 1328 (1990). .3X. DcIla\.cn JI, c,f (I/: Antibiotic and steroid therapy of ma+ sivc systemic bacillus (:alnrc,ttc,-(:lli.rin (BCC) toxicit!: J Ural 1992. ill 1jrcs.s. 39. Torti FM, PI (11: Alpha-intrrfrron in superficial bladder cancer: a Northern California Oncolok? Group Study, J Clin Oncol 6: 476 (1988). 40. Glashan RW: A randomized controlled study of intravesical alpha-2h interferon in carcinoma in situ of the bladder. J Urol 144: 658 (1990). 41. Nseyo UO: Photodynamic therapy of superficial transiUrolok? Grand Ro~mtk 35: 3 i 1990). tional cdl carcinoma (Xc:). 42. Benson RC Jr.: Treatment of bladder cancer with hematoporphyrin derivatives and laser light, Urology (suppl) 31: 10 (1991). 43. Nseyo (JO: Photodynamic therapy, Urol Clin North Am 1991, in press. 44. Jurincic CD, Engelmann U. Gasch J, and Kippel KF: Inmunotherapy in bladder cancer with keyhole-limpet hemocyanin: a randomized study, J Urol 139: 723 (1989). 4.5. Flarnm J. Bucher A, Holt W, and Albrccht W: Recurrent superfical transitional cell carcinoma of the hladder: adjuvant topical chemotherapy versus immunotherapy. A prospective randomized trial, J Urol 144: 260 (1990). 46. Pizza G, ct al: Tilmor regression after intralesional injection of intcrlcukin-2 (11,-a) in bladder cancer: preliminary report. lnt J (:anccr 34: 3.511(19X4). 47. Iluland 1:. and IIlllantl 11: I,ocal continlioll.\ hi&dose ilrtcrlcllkin 2: a nc\v thrarapclltic motlcl for the trc,atmcnt of ad\ an& bladder carcinoma. Cancer Rcb 49: 5469 (1989).
URoI.o(:l
: AI’RII.1!1!)2
VOI,ITlE
SSSIN.
NUMI%ER -l
CURRENT PERSPECTIVES ON DIAGNOSIS AND TREATMENT OF SUPERFICIAL BLADDER CANCER DONALD L. LAMM, M.D. GREG GRIFFITH, M.D. LOREEN L. PETTIT, M.D. UNYIME 0. NSEYO, M.D.
From the Department of Urology, Health Science Center, West Virginia University, Morgantown, West Virginia
An estimated 500,000 persons in the United States are living with bladder cancer, making it the fourth most prevalent noncutaneous malignancy. Three fourths of patients present with superficial disease which is amenable to complete surgical resection. However, disease will recur in more than 75 percent of these patients following resection. Although improvements in diagnosis and treatment account for much of the increase in prevalence of bladder cancer, the number of new cases continues to rise each year. In 1991 an estimated 50,200 persons were diagnosed with bladder cancer and 9.500 died of the disease. ’The most frequent age of onset is in the mid sixties, and men are affected three times as often as women. Transitional cell carcinoma accounts for over 90 percent of bladder malignancies. followed by squamous cell carcinoma (5 % ), adenocarcinoma ( < 2 % ) ~ and rhabdomyosarcoma (< 1% ) . Etiology Bladdler cancer was one of the first malignancies shown to result from exposure to chemical Beta-naphthylamine, previously carcinogens. associated with aniline dyes and used as an antioxidant in the rubber industry, is one of several potent bladder carcinogens which have been identified and consequently largely removed from the modern workplace. Epidemiologic studies, however, show continued increased risk in a wide variety of occupations having exposure to such substances as gasoline, paints, oils, chromium, and zinc.2 Though industrial carcinogerrs are important, a much greater number of people are exposed to the known bladder carcinogen, tobacco. It has been estimated that
over one half of the bladder cancer cases in men and one quarter to one third of the cases in women result from cigarette smoking. Evidence suggests that smokeless tobacco is also a bladder carcinogen. Additional risks for bladder cancer include chronic infection and inflammation, phenacetin abuse, cyclophosphamide, and pelvic irradiation. Even increased water consumption in some areas of the world has been associated with an increased risk of bladder cancer, an observation which points out the futility of attempts to completely eliminate all risk factors for cancer. While viral oncogenes have been identified in transitional cell carcinoma as well as several other cancers, such material is thought to be an intrinsic component of the vertebrate genome. Though viral oncogenes are apparently an integral part of the process of malignant transformation, there is no evidence that viral infection per se results in bladder cancer. Clinical Features Eighty percent or more of patients with bladder cancer present with hematuria. Intermittent gross total painless hematuria is typical, and microscopic hematuria is common. The intermittent nature of bleeding should be stressed, since patients and physicians alike can be mistakenly reassured when hematuria resolves. The patient who presents with advanced disease and a history of a previous episode of hematuria which was not fully evaluated is a tragedy which is repeated much too often. Symptoms of bladder irritability such as urinary frequency, urgency, and dysuria occur
in as many as one third of patients. Such symptoms mimic cystitis and prostatitis. Tumors of higher grade, including carcinoma in situ, have an increased propensity to cause such irritative symptoms. Fortunately, higher grade tumors, especially carcinoma in situ, are more likely to have a diagnostic urinary cytology. Urinary cytology, therefore, is a useful screen for bladder cancer in these patients. Symptoms of advanced disease including weight loss, abdominal mass, suprapubic or flank pain, and lymphedema are uncommonly seen today. Diagnosis Cystoscopic examination of the bladder continues to be the primary diagnostic tool since urinary cytology and imaging studies have high false-negative rates. Flexible cystoscopy can be accomplished without anesthesia in almost any patient, but rigid cystoscopy provides a clearer view of the bladder. It is axiomatic that the entire surface of the bladder should be carefully and closely. viewed, and a 120-degree lens should be used if the anterior bladder neck is not visualized with the right-angle lens. A high degree of suspicion is appropriate, and biopsies of raised, roughened, or reddened areas are best done with cupped forceps. Often one or two biopsies can be done without anesthesia, but patients with a high risk for bladder cancer are best examined and biopsy done under anesthesia so that completeness is not compromised by concern for patient discomfort. Bimanual examination under anesthesia is also an integral part of clinical staging, and sometimes even small superficial-appearing tumors can be associated with an unsuspected, nonvisualized, but palpable mass. Even careful and expert cystoscopic examination may fail to diagnose bladder cancer, as carcinoma in situ may be entirely normal in appearance. Most bladder tumors are more red in color than surrounding urothelium and can be seen from a distance. Tumors that are exactly the same shade as the rest of the bladder can be easily missed unless the bladder wall is inspected from close distance (within a few centimeters). Fortunately, urinary cytology is almost invariably positive in patients with carcinoma in situ since tumor cells are poorly differentiated, and have defective intercellular adherence and readily slough off. Indeed, in some cases the diagnosis of carcinoma in situ is more easily made with urinary cytology than bladder
biopsy, since biopsy specimen may show, only the denuded, inflamed bladder wall.‘~ Methylene blue has been used to stain transitional cell carcinoma and facilitate visualization and selection of biopsy sites. This technique is most useful in patients who have a positive cytology and no visible tumor. A solution of 0.2% methylene blue is placed in the bladder for ten minutes prior to cystoscopy. Transitional cell carcinoma and area of inflammation can be identified by blue staining. Random bladder biopsy specimens are useful in the management of bladder cancer. Biopsy specimens are taken of the margins of tumors, visibly suspicious areas, normal-appearing urothelium at multiple preselected sites such as the lateral walls, dome, posterior wall, trigone, and bladder neck, and, importantly, the prostatic urethra. Atypia or carcinoma in situ are poor prognostic signs,4 and up to 40 percent of patients undergoing cystoprostatectomy are found to have transitional cell carcinoma in the prostatic urethra. 5 The latter is of particular importance with the advent of orthotopic bladder substitution procedures where recurrence of tumor in the urethra can be devastating. In addition to urinary cytolo&T, which is highly variable in accuracy at different institutions, some have used flow cytometry, quantitative fluorescence image analysis (QFIA), rnonoclonal antibody immunocytolob3/, cluantitation of nuclear roundness and nuclearlcytoplasmic ratio, and fibrin degradation product (FDP) analysis to aid the diagnosis of bladder cancer. In our experience, FDP is more accurate than flow or QFIA. Recently immunocytology has been reported to have a 90 percent sensitivity compared with 70 percent for standard cytology and less than 50 percent for flow cvtometry.” Currently, however, these additional diagnostic techniques are generally considered investigational, and their place in routine clinical management remains to be defined. Intravenous urography (IVP) rernains the mainstay of radiographic evaluation in bladder cancer. The IVP provides efficient visualization of the upper urinary tract and is useful in the differential diagnosis of hematuria. While upper urinary tract tumors occur in only 2 to 3 percent of patients with bladder cancer,7 oarcinema in situ occurs more frequently and a baseline IVP or retrograde pyelogram is needed to demonstrate upper urinary tract anatomy. For superficial tumors not invading the detrusor muscle, additional imaging studies such as
T. (0)
T, (4
T
T,,
T,,
CC)
(6)
Mucosa Submucosa
Metastases M (0)
N-
(D. CD,
of Jewett-Strong bladder cancer staging .s!pF’I(:uHt~:1. Mar.shall:s modification tvm. Adapted from Skinner DC: Current state of classification and staging of hladdcr cancer. Cancer Res 37: 2838 (1977).
cystoglram, pelvic computed tomography, magnetic resonance imaging, ultrasonography, and bone scans are not necessary and not cost effecti\,e. Surgery Excisional transurethral biopsy (resection) is diagnostic, therapeutic, and essential for accurate staging. Transurethral surgery requires extensive experience and endoscopic training as well as considerable manual dexterity. Resection is preferably started in relatively safe areas, avoiding the dome and lateral walls overlying the obturator nerve until all other tumors have been removed so that the procedure can be terminated quickly if bladder perforation occurs. Excessive cautery current should be avoided to prevent charring of the specimen, but sufficient current should be used to permit smooth, easy cutting. Muscle should be included in the specimen to permit accurate staging, and care is taken to avoid distention of the bladder so that these specimens can be taken without bladder perforation. Areas of carcinoma in situ are fulgurated, and the roller electrode is used to fulgurate the tumor base and margins of resection. After resection of all visible tumors, the ‘IO-degree lens is reinserted to confirm that resection is complete. Pathologic Examination
and Staging
Pathologic review should provide information important to clinical management (Figs. 1
and 2). Both grade and stage correlate with prognosis. Grade I tumors rarely progress to muscle invasion; only 2 percent of grade I Stage Ta tumors and 7 percent of grade I Stage Tl tumors progress. By contrast, progression of grade III tumors is common: 25 percent for grade III Stage Ta and 48 percent for grade III Stage Tl. Thirty percent of tumors with lamina propria invasion, Stage Tl, will progress in less than four years. 4 If muscle invasion is present, aggressive treatment rather than intravesical therapy is required. Stage T2 tumors, invading less than half way through the cletru$,or muscle: Stage T3a tumors, invading into the $,econd half of detrusor muscle; and Stage T3b tllmora. extending into perivesical fat, should (in our opinion) preferably be treated with radical c!-stectomy. Indications
for Intravesical
Therapy
Not all patients with superficial bladder cancer require intravesical therapy. Patients with a solitary low-grade Stage Ta tumor are at low risk of recurrence and progression and can be TARI.E I. _-___
Indications
for intraoc&cal
Multiple primary tumors Multiple tumor recurrences (:rade III tumor Stage Tl tumor Positive cvtolo53
therapy
Carcinoma
-------
in situ
Papillary tumors without invasion Invasion of lamrna propria
-------
__c--t__-.
Superficial muscle invasion Deep muscle invasion ------Invasion of perivesicular fat __-_----Invasion of prostate, vagina Fixed pelvic
B
C
uterus
to or abdominal
Pelvic
wall
A
A
I
_I-
nodes
Distant
metastases
Nodes above aortic bifurcation
FIGURE2. Comparbons of American and TNM staging systems for bladder cancer. Adapted from Skinner DG: Current state of classification and staging of bladder cancer, Cancer Res 37: 2838 (1977).
spared the expense and morbidity of intravesical therapy as well. Clear indications for intravesical therapy include multiple primary tumors, tumor recurrence, grade III tumor, Stage Tl tumor, positive post-resection urinary cytology, and dysplasia or carcinoma in situ (CIS) on random biopsy specimen (Table I). The goals of intravesical therapy are the prevention or postponement of tumor recurrence, eradication of residual unresectable papillary transitional cell carcinoma or carcinoma in situ, prevention of tumor progression, reduction of the need for radical cystectomy, and maintenance and prolongation of good quality life. While prevention of tumor recurrence is a significant achievement, prevention of tumor progression is by far the most important goal. Intravesical
Chemotherapy
Effective intravesical chemotherapy dates back to 1955 when thiotepa was first instilled in
304
the bladder to treat superficial bladder cancer.* Since that time controlled studies have demonstrated that four commonly used intravesical cytotoxic chemotherapies are effective in the treatment of residual tumor and the prevention of tumor recurrence. These intravesical chemotherapies are: thiotepa, doxorubicin (Adriamycin), mitomycin C (Mutamycin), and ethoglucid (Epodyl). (Ethoglucid is not commercially available in the U.S.) Published response rates in 1,582 patients with residual papillary transitional cell carcinoma show average complete response rates of 29 percent for thiotepa, 38 percent for doxorubicin, 47 percent for mitomycin C, and 55 percent for ethoglucid.g While these data suggest that ethoglucid and mitomycin may be more effective than thiotepa, prospective controlled studies have failed to confirm the superiority of newer chemotherapies over thiotepa. Nineteen randomized, controlled, prospective studies have compared intravesical chemotherapy
with surgery alone. B I9 Six of 10 thiotepa studies showed a statistically significant advantage for intravesical thiotepa, and reduction in tumor recurrence averaged 17 percent. Two of four doxorubicin studies and two of five mitomycin studies ‘were statistically significant, with relative advantages of tumor recurrence of 18 percent and 16 percent, respectively. Multiple studies comparing one intravesical chemotherapy with another have failed to confirm that any of the newer chemotherapies are significantlv better. Extensive data now confirm that intravesical chemotherapy reduces the rate of short-term tumor recurrence by a modest 16 percent to 18 percent. Unfortunately, the long-term rate of tumor recurrence and, more importantly, the rate of disease progression are not reduced. With over 3,000 patients enrolled in controlled studies,g 2o evidence fails to supplort the conclusion that intravesical chemotherapy reduces the rate of tumor progression. One approach to improve the benefits of intravesical chemotherpay has been to keep patients on maintenance regimens. Recently, reports by, Flammzl and Huland et dz2 demonstrate that maintenance doxorubicin or mitomycin offer no benefit over shorter courses. Indeed. evidence suggests that very early shortcourse lchemotherapy may provide the highest relative benefit.23 With thiotepa, the two studies showing the greatest advantage, and indeed the only study to show a statistically significant advantage of chemotherapy at the p < 0.001 level, used early postoperative thiotepa. 13.23 Studies with thiotepa also suggest that the patients who benefit most from intravesical chemotherapy are those with low-grade tumors.“’ Intravesical
Immunotherapy
It is a mistake to group chemotherapy with immunotherapy since the mechanisms of action, th,e principles of treatment, and the potential benefits of therapy are distinctly different. The commonly used intravesical chemotherapies, with the exception of the intercalating agent doxorubicin, are alkylating agents, and all have a similar mechanism of action. Immunotherapy, as exemplified by the first effective immunologic treatment for bladder cancer, bacillus Calmette-Guerin (BCG), stimulates immune defenses. While cytotoxic chemotherapy is effective only against existing malignancy, immunotherapy has the potential to induce specific immunity to tumor, making pos-
sible the prevention of tumors that have not yet developed. Two immunotherapies are commercially available in the United States: BCG and alpha-interferon, BCG
immunotherapy
Following the demonstration in the early 1970s that BCG could cause regression of cutaneous malignancies, a number of investigators independently evaluated BCG irnmunotherapy in bladder cancer. Morales, Eidinger, and Bruce24 were the first to report clinical success in 1976, when they observed a l%fold reduction in tumor recurrence in patients given a sixweek course of intravesical and percutaneous BCG. BCG immunotherapy has subsequently been confirmed by investigators around the world to be highly effective in the reduction of tumor recurrence, the treatment of residual papillary transitional cell carcinoma, and, most importantly, the treatment of carcinoma in situ. Response rates in the treatment of residual papillary disease average 55 percent.“” In the treatment of carcinoma in situ, with 663 patients treated in fifteen studies,“’ x the average complete response rate is ‘73 percent. higher than that achieved with any other intravesical agent. In the prevention of tumor recurrence. the relative benefit of BCC is 4Fj percent in 456 patients. and four of five controlled studies are statistically significant (p < 0.001) .rfi 27 3o Direct prospective randomized comparisons of BCG with intravesical chemotherapy have found it to be significantly superior to thiotepa, doxorubicin, and mitomycin in the prevention of tumor recurrence.31 33 When intravesical chemotherapy is used prophylactically, tumor recurrence is delayed, but after five years the percentage of patients who have recurrence is not decreased.“” With BCG immunotherapy, however, benefits appear to be long-term. For example, in the Southwest Oncology Group study comparing BCG with doxorubicin in patients with rapidly recurring transitional cell carcinoma, only 17 percent of patients were estimated (Kaplan-Meier) to be tumor-free at five years compared with 37 percent of BCG-treated patients. In patients with carcinoma in situ, the difference was even more pronounced, 18 percent versus 45 percent (p < 0*0001).:~~ Tfimor progression
While chemotherapy has failed to reduce tumor progression, evidence suggests that immunotherapy with BCG does in fact reduce
tumor progression. Experience with 90 nonranhas shown that the domized patients progression to muscle invasion can be reduced from 8 percent in controls to 3 percent with BCG therapy., ‘I4 This difference is not statistically significant, but the reduction in invasion of lamina propria from 23 percent to 6 percent was significant. In randomized studies, Herr et al. 36 observed a delay and reduction in muscle invasion from 35 percent in controls to 28 percent with BCG treatment (p < O.Ol), and Pagano et a1.3”observed a reduction from 17 percent to 4 percent (p < 0.001). The need for cystectomy was also significantly reduced in Herr’s study, and despite the more frequent and earlier use of cystectomy, mortality was significantly reduced in the BCG group from 32 percent to 14 percent.“5
BCG complications While 95 percent of patients tolerate BCG without significant toxicity, serious and even fatal reactions can occur. Septic reactions, characterized by fever, hypotension, disseminated intravascular coagulopathy, and multi-organ failure have been temporally associated with BCG administration. Such reactions are typically associated with traumatic catheterization or intravenous absorption of BCG.37 Recent evidence suggests that hypersensitivity is a significant component of this toxicity, and current recommendations for treatment are isoniazid (330 mg), rifampin (600 mg), and prednisolone (40 mg) daily.38
Alpha-interferon The remarkable efficacy of immunotherapy with BCG has pointed out the general potential of immunotherapy in the treatment of superficial bladder cancer and raises an obvious question: can alternative immunotherapies produce the benefits of BCG without the toxicity? Several immunotherapeutic agents are currently being evaluated around the world. However, the only commercially available immunotherapeutic alternative to BCG in the United States is alpha-interferon. Considerable evidence has now accumulated to indicate that recombinant human interferon alpha-2b has activity in the treatment of transitional cell carcinoma. In a phase I-II trial, Torti et aZ.3y evaluated interferon alpha-2b in heavily pretreated patients with papillary and in situ transitional cell carcinoma. In patients with papillary transitional cell carcinoma, complete response was observed in 4 of 16 pa-
tients, 3 of whom had previously failed to respond to intravesical chemotherapy. As expected with immunotherapeutic agents, response in carcinoma in situ (CIS) was higher. Nine of 19 CIS patients (47 % ) had complete response to interferon, though 3 of these patients had subsequent grade I papillary transitional cell carcinoma. Patients with prior chemotherapy had a complete response rate in CIS which was not significantly different from those who had not had prior chemotherapy. Dosage of interferon alpha-2b in this study ranged from 50 to 1,000 million units given weekly for eight weeks. Complete responses at the lower doses (50 to 100 million units) occurred as frequently as responses at doses of 400 to 1,000 million units, confirming that high immunotherapeutic dose does not necessarily correlate with high therapeutic activity. Five of 10 patients with complete response remained disease free at 18 + to 37 + months. Importantly, no serious toxicity was observed in this study. No patient had hematuria, dysuria, or myelosuppression, and only 15 of 55 patients (27%) had mild flu-like symptoms. The maximum tolerated dose was not reached at 1,000 million units. In a subsequent phase III trial, Glashan40 randomized 87 patients with biopsy-proved carcinoma in situ to receive 10 or 100 million units of interferon alpha-2b weekly for twelve weeks followed by monthly instillations to one year. Eighty-five patients were subsequently evaluable for tolerability and 80 for drug activity. Patients could have received a variety of surgical and intravesical therapies prior to entry into this trial. Two of 37 evaluable patients (5 %) receiving low-dose interferon alpha-2b had complete response, while 20 of 43 evaluable patients (47%) receiving high-dose interferon alpha-2b had complete response (p < 0.0001). In the low-dose group, an additional 12 of 37 patients (32%) had evidence of complete resolution of carcinoma in situ on rebiopsy, but had residual positive findings on urinary cytologic examination. In the high-dose group, an additional 9 patients had complete response by biopsy, but not by cytology. It is notable that 6 of 9 patients previously treated with BCG showed objective responses to interferon, including 2 patients who achieved complete responses to high-dose therapy. In the low-dose group, disease progression was observed in 14 of 37 patients (38 %) compared with only 6 of 43 in the high-dose group (14 %). The duration of
has now ranged from six nlontlls to ov(‘r f\vo J’ears. S!sterrlic absorption of interferon alpha-2h in this stud!. was not observed. As in the earlier studv b;; X)rti rat al. .‘I’no local toxicit), oc~curred and flu.-like s>,rnptoms were uncommon. found in onl!. ;S percent of the low-dose and I7 percent of the high-dose subjects. There were no cases of patients discontinuing treatment as a consecltlellce of arl\rerse reactions to interferon alpha211.
co~rrplei~~ rtyxmsc’s
Xlternative
Treatments
Several in\.estigators have demonstrated the efficaq of photodynamic therapy (PDT) in ablating papillaq~ transitional cell carcinoma (‘XC) and carcinoma in situ of the urinaq bladder. and in preventing recurrence in patients \vlro halve failed conventional intravesical therap!, for superficial transitional cell carcilloma. A single treatment with PDT has been rcJporte,d to eradicate papillary TCC in ‘70 to 9S percent of l’atients. 4’However, complete tumor ablation N.;~s generally limited to patients who had tumors that were less than 2 cm in diameter. Response rates of 80 to 100 percent are reported in patients with refractory CIS treated with I’1YI’.2’ With a mean follow-up of 19.4 months (range 6 to 50 months), we have obser\:ed tumor recurrence in 2 of 11 patients (1X “%) with recurrent TCC treated prophylacticall\. with l’I?T I . ,1.X Kqholc~
lil,ipct
iwnocyanin
C;on~;iderat:,le laboratory and clinical evdence now suggests that the highly antigenic respirai.r)r!. pigment (hemolymph) of the mollust Mqathrlria crenulata has significant antitumor acti\GtJ: Studies in Europe have suggested that intravesical and percutaneous kq.hole linlpet hemocyanin (KLH) results in bladder tumor recurrence rates which are lower than those observed with mitomycin and equal to those:, obser\red with ethoglucid.44 4r, Other
I wm rtrdogicdl~~
active agvn ts
Originally termed T-cell growth factor, interlcukin !Z(II,-2) is produced by helper T lymphoc!,tes al Id serves to stimulate lymphocyte proliferatioir . IIltralesional IL-2 was reported b> Pizza ~1 nl:+” l-0 result in complete tumor regression in 3 of 6 patients receiving 4,000 units of II ,-2. HIlland”’ has similarly observed complete rqxm:;? in 1 of 4 patients given continuous in-
fusion intravesical IL-2, clearl!, suggesting activity of IL-2 in bladder cancer. Other agents with a suggestion of irnmrmologic activity in bladder cancer include maltose tetrapalmitate OK-432. a lyol)hilized attcanuated streptococcus vaccine. and the interferon inducers polyI:C and bropirimine. Conclusions Intravesical chemotherapy results in tumor regression in one quarter to one half of patients with papillary and in situ transitional cell carcinoma of the bladder. Used prophylactically, chemotherapy reduces short-term tumor recurrence by 16 percent to 18 percent, but does not appear to reduce long-term recurrence. disease progression, or mortality. Efforts are Ilnderwa) to improve intravesical chemotherapy, and multiple approaches not available to systemic chemotherapy are possible. Immunotherapy, as exemplified 1~~7 BCG. has a mechanism of action which is different from classic cytotoxic chemotherapy. B(:G treatment results in regression of 50 percent to 80 percent of papillary and in situ carcinomas. and reduces tumor recurrence by as much as 50 percent. The benefits of BCG immunotherapy appear to be long-term in some patients, and controlled studies suggest that tumor progression and even mortality can be reduced. Enthllsiasm for widespread use of BCG is. however, tempered by concerns regarding significant toxicity. Alternative immunotherapies have the prospect of being highly effective as well as less toxic. Although few alternative immunotherapies are commercially available in the U.S. at this time, research is underway to develop these agents. Interferon alpha-2b is one agent Jxhich has demonstrated anti-tumor activity in papillary (25 % complete response) and in situ (4’i % complete response) carcinoma. Further research, and possibly the use of combination immunotherapies, should significantly improve treatment options in the hlture. Health
Science Center. Koom 2237 West Virginia lJniversit\, Morgantown, West Virginia 26506 (DR. LAMM)
4. Heney NM, et al: Superficial bladder cancer: progression and recurrence, J Urol 130: 1083 (1983). 5. Wood DP, Montie JE, Vandcrburg-Medendorp S, and Lcvin HS: Transitional cell carcinoma of the prostate in cystoprostatectomy specimens removed for bladder cancer. J Urol 141: 346 (1989). 6. Klan R, Huland E, Baisch H, and Huland ff: Sensitivity of urinary quantitative immunocytology with monoclonal antibody 486 P3112 in 241 umelected patients with bladder carcinoma. J Urol 145: 495 (1991). 7. hlalkowicz SB, and Skinner IX:: Dcvclopmcnt of upper tract carcinoma after cystrctomy for bladder carcinoma. Urolog! 36: 20 (1990). 8. Bateman JC: Chemotherapy of solid tumors with trimethylene triphosphoramide, N Engl J Med 252: 879 (1955). 9. Kowalkowski TS, and Lamm DL: Intravesical therapy of superficial bladder cancer, in Resnick M (Ed): Current Trends in Urology, Baltimore, Williams and Wilkins, 1989. 10. Prout GR, et al: Long-term fate of 90 patients with supcrficial bladder cancer randomly assigned to rcccive or not receive thiotepa, J Urol 130: 667 (1983). 11. Medical Research Council: The effect of intravesical thiotepa on the recurrence rate of newly diagnosed superficial bladder cancer, Br J Urol 57: 680 (1985). 12. Niijima T, Akaza H. Koisok K, and the Japanese Urologic Cancer Research Group for Adriamycin: Randomized clinical trial on chemoprophylaxis of recurrence in cases of superficial bladder cancer, Cancer Chemother Pharmacol (Suppl) 2: 579 (1983). 13. Zincke H, et al: Influence of thiotepa and doxorubicin instillation at time of transurethral surgical treatment of bladder cancer on tumor recurrence: a prospective, randomized. double blind, controlled trial, J Urol 129: 505 (1983). chemotherapy of superficial 14. Kurth KH, et al: Adjuvant transitional bladder carcinoma: preliminary results of a European Organization for Research on Treatment of Cancer randomized trial comparing doxoruhicin hydrochloride, ethoglucid and transurethral resection alone, J Urol 132: 258 (1984). 15. Rubben H, et al: Natural history and treatment of low and high risk superficial bladder tumors, J Ural 139: 283 (1988). randomized study of aclju16. Ruhhen II, et al: Prospective vant therapy after complete resection of superficial bladder cancer: mitomycin C versus BCG Connaught versus TUR alone, in deKernion JB (Ed): International Society of Urology Reports, New York, Churchill Livingstone, 1990, chap 3. 17. Huland H, and Otto U: Mitomycin instillation to prevent recurrence of superficial bladder carcinoma, Eur Urol 9: 84 (1983). 18. Kim HH, and Lee C: lntravesical mitomycin C instillation as a prophylactic treatment of superficial hladder tumor (abstr.), J Urol 139: 245A (1988). 19. Tolly DA, et al: Effect of intravesical mitomycin C on rccurrence of newly diagnosed superficial bladder cancer: an interim report from the Medical Research Council subgroup on SIIperficial bladder cancer, Br Med J 296: 1759 (1988). 20. Newling D: Intravesical therapy in the management of ~(1. perficial transitional cell carcinoma of the bladder: the experirncc of the EORTC GU group, Br J Cancer 61: 497 (1990). 21. Flamm J: Long-term versus short-term doxorubicin hydrochloride instillation after transurethral rcycction of superficial bladder cancer, Eur Urol 17: 119 (1990). 22. Huland H, ~1 al: Comparison of different schcdulrs of cytostatic intravesical instillations in patients with superficial bladder carcinoma: final evaluation of a prospective multicentcr stud) with 419 patients, J Urol 144: 68 (1990). 23. Burnand Kc:. cat ~1: Single-dose intravcsaical thiotcpa as an adjuvant to cystodiathcrm!in the treatment of transitional ccl1 bladder carcinoma. Br J Ural 48: 55 (1976). 24. Morales A, Eidinger D, and Bruce A\V: Intracavitary bacillus Calmette-G&in in the treatment of superficial hladdcr tumars, J Ural 116: 180 (1976).
308
25. Sosnowski JT. and Lanrm DL: Immunotherapy of bladder carcinoma. in Crawford ED, and Das S (Eds): Current Cenitourinary Cancer Surgery. Philadelphia, Lea and Febiger, 1990, chap 47. 1’480. 26, I,amm DL: Rc.sulth of clinical trials of B(:G thchrap): AU.4 X,da> 4: 22 (1991). 27. Lamm DL: Bacillus Calmette-Gu&in immunotherapy for bladder cancer, J Urol 134: 40 (1985). 28. Herr HW, ct (I/: Long-term effect of intravesical bacillus Calmettc-Guerin on flat carcinoma in situ of the bladder, J Urol 134: 40 (198.5). 29. Paaano E: ct al: Long-term effect of intravcsical bacillus Calmctte-G&in regime in superficial bladder cancer therapy: is it effective?, J Urol 146: 32 (1991). 30. Herr IIW, rt (11: Experience with intravesical bacillus Calmette-Gukrin therapy of superficial bladder tumors, Urology 25: 119 (1985). 31. Fauhiainen K, Rintala E, and Alfthan 0: Immunotherap) (BCG) versus chemotherapy (MMC) in intravesical treatment of superficial urinary bladder cancer, in DeKcrnion JB (Ed): International Society of Urolok~ Reports, New York, Churchill Livingstonc, 1990, chap 2, 1’ 13. 32. Martinez-Pirieiro JA, et al: Bacillus Calmette-Gukrin versus doxoruhicin versus thiotepa: a randomized prospective stud) in 202 patients with superficial bladder cancer. J Urn1 143: 502 (1990). trial of intravcsical dox33. Lamm DL, et al: A randomized orubicin and immunotherapy with bacillus Calmette-G&in for transitional cell carcinoma of the bladder, N Engl J Med 325: 1205 (1991). .34. Reynolds R, Stogdill UD, and Lamm DL: Disease progression in BCG-treated patients with transitional cell carcinoma of the bladder (ahstr), J Urol 133: 211A (1985). 3s. Iferr W, ct al: Bacillus Calmette-G&in therapy alters the progression of superficial bladder cancer, J Clin Oncol 6: 1450 (1988). 36. Pagano F, et al: A low-dose bacillus Calmette-G&in regimen in superficial bladder cancer therapy: is it effcctivc?, J U& 146: 32 (1991). .37. Rawls iv, pt al: Fatal sepsis following intravesical bacillus Calmette-G&in administration for bladder cancer, J Urn1 144: 1328 (1990). .3X. DcIla\.cn JI, c,f (I/: Antibiotic and steroid therapy of ma+ sivc systemic bacillus (:alnrc,ttc,-(:lli.rin (BCC) toxicit!: J Ural 1992. ill 1jrcs.s. 39. Torti FM, PI (11: Alpha-intrrfrron in superficial bladder cancer: a Northern California Oncolok? Group Study, J Clin Oncol 6: 476 (1988). 40. Glashan RW: A randomized controlled study of intravesical alpha-2h interferon in carcinoma in situ of the bladder. J Urol 144: 658 (1990). 41. Nseyo UO: Photodynamic therapy of superficial transiUrolok? Grand Ro~mtk 35: 3 i 1990). tional cdl carcinoma (Xc:). 42. Benson RC Jr.: Treatment of bladder cancer with hematoporphyrin derivatives and laser light, Urology (suppl) 31: 10 (1991). 43. Nseyo (JO: Photodynamic therapy, Urol Clin North Am 1991, in press. 44. Jurincic CD, Engelmann U. Gasch J, and Kippel KF: Inmunotherapy in bladder cancer with keyhole-limpet hemocyanin: a randomized study, J Urol 139: 723 (1989). 4.5. Flarnm J. Bucher A, Holt W, and Albrccht W: Recurrent superfical transitional cell carcinoma of the hladder: adjuvant topical chemotherapy versus immunotherapy. A prospective randomized trial, J Urol 144: 260 (1990). 46. Pizza G, ct al: Tilmor regression after intralesional injection of intcrlcukin-2 (11,-a) in bladder cancer: preliminary report. lnt J (:anccr 34: 3.511(19X4). 47. Iluland 1:. and IIlllantl 11: I,ocal continlioll.\ hi&dose ilrtcrlcllkin 2: a nc\v thrarapclltic motlcl for the trc,atmcnt of ad\ an& bladder carcinoma. Cancer Rcb 49: 5469 (1989).
URoI.o(:l
: AI’RII.1!1!)2
VOI,ITlE
SSSIN.
NUMI%ER -l
