0022-534 7/92/14 73-0596$03.00/0 Vol. 147, 596-600, March 1992
THE JOURNAL OF UROLOGY Copyright© 1992 by AMERICAN UROLOGICAL ASSOCIATION, INC.
Printed in U.S.A.
INCIDENCE AND TREATMENT OF COMPLICATIONS OF BACILLUS CALMETTE-GUERIN INTRAVESICAL THERAPY IN SUPERFICIAL BLADDER CANCER DONALD L. LAMM, AD P. M. VAN DER MEIJDEN, ALVARO MORALES, STANLEY A. BROSMAN, WILLIAM J. CATALONA, HARRY W. HERR, MARKS. SOLOWAY, ADOLPHE STEG AND FRANS M. J. DEBRUYNE From the Departments of Urology, West Virginia University School of Medicine, Morgantown, West Virginia; University Hospital Nijmegen, Nijmegen, The Netherlands; Queen's University Kingston, Kingston, Ontario, Canada; UCLA Center for Health Sciences, Los Angeles, California; Washington University School of Medicine, St. Louis, Missouri; Memorial Sloan-Kettering Cancer Center, New York, New York;University of Miami, Miami, Florida, and Hopital Cochin, Paris, France
ABSTRACT
Intravesical therapy with bacillus Calmette-Guerin (BCG) has proved to be more effective in the prophylaxis and treatment of superficial bladder tumors and carcinoma in situ than most chemotherapeutic agents. Compared to intravesical chemotherapy, instillations with BCG provoke more local and systemic reactions. In addition to the commonly induced granulomatous inflammatory changes in the bladder, which produce irritative symptoms, this therapy may cause systemic side effects varying from mild malaise and fever to, in rare instances, life-threatening or fatal sepsis. We report the incidence and varieties of toxicities in 2,602 patients treated with intravesical BCG. Side effects are classified according to local and systemic toxicity. Treatment options vary according to the severity of toxicity from delaying or withholding instillations to treatment with antituberculous drugs for up to 6 months. In general, 95% of the patients have no serious side effects. Recognition of risk factors, particularly traumatic catheterization or concurrent cystitis, that result in systemic BCG absorption, as well as the prompt and appropriate treatment of early side effects should significantly decrease the incidence of severe toxicity. KEY WORDS:
bladder neoplasms, BCG vaccine, carcinoma in situ
Intravesical instillations of bacillus Calmette-Guerin (BCG) have been shown to be effective treatment of and prophylaxis against recurrent stages Ta and Tl tumors and carcinoma in situ. A variety of treatment schedules, BCG preparations and doses have been used. 1 The optimal BCG preparation, treatment schedule and dose have not yet been identified. It is possible that optimal therapy differs from patient to patient as a result of tumor and host factors that also remain to be identified. Toxicity has been reported to be substantially greater with intensive regimens but severe side effects have also bee·n observed after only a few instillations. 2 • 3 In many series the reported toxicity of intravesical BCG therapy is greater than that of intravesical chemotherapy. However, prospective randomized comparisons of BCG and chemotherapy have demonstrated no substantial differences in local toxicity. Considering risk and benefit for the individual patient, BCG should not be administered to patients with low stage, low grade (stage pTa, grade 1) unifocal or primary tumors. The risk for tumor recurrence or progression is low in these tumor categories. The majority of patients tolerate BCG instillations well but adverse effects can and do occur. While systemic complications of BCG are uncommon their variety and potential severity demand our attention. We document the incidence of BCGinduced side effects and serious complications, and devise a rational approach to their diagnosis and management. We update our previous series reported in 1986 in which cystitis occurred in 91 % of the patients, hematuria in 43%, low grade fever in 28%, malaise in 24% and nausea in 8%. Fever of more than 39.5C was observed in 3.9% of the patients, granulomatous prostatitis in 1.3%, granulomatous pneumonitis or hepatitis in 0.9%, arthritis or arthralgia in 0.5%, epididymo-orchitis in 0.2%, bladder contracture in 0.2%, hypotension in 0.1% and Accepted for publication July 12, 1991.
cytopenia in 0.1 %. There were differences in the frequency of complications using various BCG preparations (Armand Frappier, Tice, Connaught and Pasteur strains). Some of these differences, however, reflect variations in dose and treatment schedule as well as differences in judgment regarding the severity of adverse effects among the individual urologists. MATERIALS AND METHODS
We expand a review of 1,278 patients reported on in 1986 in which the reactions are described among 1,324 patients treated by multiple investigators in Canada, the United States and Europe. 4 The initial review tabulated both series and detailed questionnaires from major investigators at the time. The current review updates and expands the previous review by adding the results of our series as reported by the European Organization for Research on Treatment of Cancer Genitourinary Group. In addition, treatment recommendations are the result of a consensus meeting of the authors held during the 1989 meeting of the American Urological Association. RESULTS
With the expansion of this experience to a total of 2,602 patients treated with the Armand Frappier, Tice, Connaught, Pasteur or RIVM strain of BCG, no significant change in the complication rate was observed. High fever (greater than 39C) was noted in 2.9% of the patients. Histologically documented granulomatous prostatitis decreased from an incidence of 1.3 to 0.9%. Major hematuria occurred in 1.0% of the patients. Granulomatous pneumonitis and/or hepatitis as a result of systemic BCG infection was observed in 0.7% of the patients, while life-threatening BCG sepsis was noted in 0.4%, arthritis and arthralgia occurred in 0.5% and skin rash in 0.3%. The incidence of ureteral obstruction (0.3 %), epididymo-orchitis (0.4%) and bladder contracture (0.2%) remained essentially
596
597
INTRAVESJ:CAL BACILLUS CALMETTE-GUERIN IN SUPERFICIAL BLADDER CANCER
unchanged. The incidence of complications in 2,602 patients is shown in table 1. DISCUSSION
BCG is the attenuated strain of the bovine tuberculous bacterium and consists of living bacilli, dead microorganisms and subcellular debris. It maintains the immunological properties and antibiotic sensitivities of the parent strain. Variability in the dose and viability can be expected among the different suppliers of BCG and even among different lots from the same supplier. 5 Storage of the vials at the correct temperature is critical for the survival of the mycobacteria. Apart from possible differences in efficacy and toxicity between the different BCG preparations it is difficult to distinguish between therapyrelated symptoms that may indicate efficacy and symptoms that may represent adverse effects. Therefore, it is sometimes difficult to define the true toxicity of this therapy. Many investigators believe that an inflammatory reaction is an important component of the response to BCG therapy. The attachment of BCG bacilli to the damaged bladder wall has been clearly demonstrated. 6 Following attachment, histological examination of the bladder mucosa reveals granulomatous inflammatory reactions and mononuclear cell infiltration predominantly in the subepithelial layer of the bladder wall. 7•8 Granulomas are commonly found in the bladder wall and also can be found in the primary draining lymph nodes of the bladder, and on rare occasions throughout the liver and lungs. It is most unusual to detect BCG microorganisms in these granulomas. 7 Granulomatous hepatitis has been reported in cancer patients after intralesional and intradermal BCG administration. Such reactions appear to be hypersensitivity responses, since viable mycobacteria have not been recovered from these lesions. 9 ' 10 Therefore, many believe that granulomas outside the primary inoculated site are the results of hypersensitivity reactions to BCG antigens. Toxic side effects that occur after BCG immunotherapy in cancer patients can be divided into local and systemic categories. Important factors for this toxicity are the route of administration, number of repeated injections and dose of BCG. The local side effects of BCG skin inoculations are well known from the extensive experience with the BCG vaccine for prevention of tuberculosis. 11 Complications from vaccination are manifested by persistence of ulceration, localized abscess formation, granuloma formation or regional lymphadenitis. Systemic complications and generalized BCG infection have been reported, especially in children with immunodeficiency syndromes. A total of 35 fatalities has been reported among more than 1.5 billion vaccinations for tuberculosis prophylaxis, 12 Almost all of these fatalities occurred in children with defects in cellular immunity. Complications of BCG vaccination in cancer therapy are relatively rare but are more frequent than in tuberculosis vaccination programs. This is probably related to the impaired TABLE 1.
Fever Granulomatous prostatitis Pneumonitis/hepatitis Arthralgia Hematuria Rash U reteral obstruction Epididymitis Contracted bladder Renal abscess Sepsis Cytopenia
immunological status of many cancer patients and to the intralesional application of BCG. In some instances intralesional administration might be equivalent to intravenous injection, since tumor nodules may be highly vascularized. 13 Fever of 40C, severe malaise, hepatic dysfunction and granuloma formation in the liver and lungs have been described after intralesional BCG injection. BCG has been administered intrapleurally for adjuvant treatment of lung cancer. Severe side effects of this therapy were observed on rare occasion and were mostly related to high doses of BCG. However, hepatic dysfunction and weight loss were reported more frequently. 14 After orally administered BCG no toxicity was observed. When viable BCG is injected intravenously severe toxicity can be encountered. Granuloma formation was observed in bone marrow, liver, lungs, spleen and lymph nodes in cancer patients treated by intravenous administration. 15 Thousands of patients with superficial bladder cancer including carcinoma in situ have been treated with BCG. Intravesical instillation has proved to be the most effective route of administration.16 The complications encountered are more frequent and more severe than those seen with vaccination for tuberculosis. Although less frequent, complications seen after intravesical instillation are comparable to those observed after intralesional injection. The symptoms, histological appearance and localization of granulomas are similar. While only 1 death per 50 million patients occurred if BCG was given for tuberculosis prophylaxis, a mortality rate of l death per 12,500 patients was observed when BCG was administered in the treatment of cancer patients. In the patients with superficial bladder cancer treated intravesically with BCG at least 7 deaths have been associated with although not conclusively caused by its use. It is unknown how many patients have been treated with BCG intravesically because not all patients are enrolled in trials. While the mortality rate in bladder cancer patients treated with intravesical BCG cannot be accurately estimated to date, it is anticipated that it will be less than l death per 12,500 patients, since intralesional injection results in intravenous absorption of BCG more frequently than topical application and, unlike many patients with other malignancies, patients with superficial bladder cancer generally have an intact immune system. Contraindications in ECG use. Intravesical BCG immunotherapy should not be used in patients suffering from active tuberculosis and it should be used with great caution, if at all, in patients with congenital or acquired immunodeficiency syndromes (AIDS), leukemia or Hodgkin's disease. Transplant recipients and patients with positive human immunodeficiency virus serology with or without clinical manifestations of AIDS should also not be treated with BCG. Finally, BCG should be avoided during pregnancy and lactation, and in cases of intractable urinary tract infection. Although sexual transmission of BCG has not been reported it has been suggested that a condom should be used during coitus for 1 week after BCG therapy. The adverse effects of intravesical BCG therapy could be clas-
Complications in 2,602 patients according to substrains of BCG
Total No.(%) (2,602 pts.)
% Armand Frappier (718 pts.)
% Tice (726 pts.)
% Connaught (353 pts.)
% Pasteur (325 pts.)
%RIVM (129 pts.)
75 (2.9) 23 (0.9)
3.8
4.7
1.8
18 (0.7)
0.4 0.7 0.3 0.4 0.6 0.4
1.0 0,8
4.7 0.2 0.6 0.6 2.4
0,6 0.6 1.2
1.8
2.1 0.0 0.8 0.0
1.0
0.4
0.9
0.0
0.2 0.2 0.2 0.4
0.0 1.2 0,6
0.0 0.0 0.8
0.0
0.0
0.9 0.0
0.2 0.0
0.0
12 (0.5) 24 (1.0) 8 (0.3) 8 (0.3) 10 (0.4) 6 (0.2) 2 (0.1) 10 (0.4) 2 (0.1)
0.0 0.0 0.1 0.0
0.1 0.6 0.0 0.4
0.0 0.3 0.0 0.4 0.3
0.0 0.0
Since definitions of side effects differ from one series to another and all complications were not considered in each series, some asumptions have been made to estimate the overall incidence of complications.
598
LAMM AND ASSOCIATES
sified as local or systemic, and subdivided into minor and major toxicity groups according to treatment considerations. Our suggested treatment of ECG-related complications is summarized in table 2. Local side effects. Local side effects of BCG instillation therapy are defined as effects confined to the bladder or those organs that are in contact with BCG bacilli. Reported side effects include bacterial cystitis (not ECG-related), drug-induced or chemical cystitis, minor and major hematuria, bladder contracture, granulomatous prostatitis, epididymo-orchitis, ureteral obstruction and renal abscess. Culture proved bacterial cystitis not specifically related to BCG is treated with antibiotics until the culture becomes negative and symptoms have resolved. We recommend withholding BCG instillations during treatment of bacterial urinary tract-infections for 2 reasons: 1) the combination of bacterial cystitis and drug-induced (BCG) cystitis can cause severe inflammatory reactions that may lead to more side effects and 2) BCG bacilli are sensitive to antibiotic therapy and a decrease in antitumor efficacy may occur. In vitro culture experiments indicate that BCG microorganisms can be eradicated by a number of antibiotics, including trimethoprim sulfamethoxazole and norfloxacin (unpublished observations). It is logical to expect that concomitant administration of antituberculous drugs would diminish the antitumor effects of BCG but animal studies have demonstrated that concomitant isoniazid therapy does not decrease the antitumor efficacy. Moreover, animal studies have clearly demonstrated that administration of excessive doses of BCG results in diminished antitumor immunity. 17• 18 Since BCG is a living organism that can survive and multiply after intravesical instillation, patients with persistent symptoms should be treated not only to prevent side effects but also to prevent a decrease in antitumor immune responses. Cystitis caused by BCG is defined as drug-induced or BCG cystitis. Drug-induced cystitis typically consists on biopsy of acute and chronic inflammation with or without granuloma formation. Patients complain of urinary frequency, urgency and pain in the bladder region. Repeated BCG administration increases the incidence and severity of cystitis. The normal bacterial urine culture remains negative. Symptoms generally start 2 to 4 hours after instillation and will typically subside without therapy within 6 to 48 hours. Relief is produced by symptomatic medication, such as phenazopyridine, propantheline bromide or oxybutynin. Drug-induced cystitis is considered by most investigators as a normal reaction to BCG therapy. In fact, when some degree of cystitis does not occur there is reason to question the adequacy of the treatment. 19 Antituberculous drugs, such as isoniazid, are not generally necessary. Postponement of instillation is advised until symptoms from the previous instillation have completely resolved. Hematuria is another local side effect often associated with drug-induced cystitis. Only on rare occasions is hematuria sufficient to require catheterization or transfusion. Hematuria is often observed after large tumor resections or in the presence of unresected friable tumors. Bladder contracture is a serious local complication. It has been observed predominantly in patients treated on a maintenance schedule but it also has been reported after multiple TABLE 2.
Fever Less Than 38.5C No treatment Hold BCG until symptoms have resolved
transurethral resections and instillations with chemotherapeutic drugs. Because of the low frequency (0.2%) of contracted bladder, and the pretreatment of most patients with multiple transurethral resections and other drugs it is difficult to state with certainty whether BCG alone causes bladder contracture. Treatment of this problem consists of withholding BCG, hydrodistension and sometimes bladder augmentation. Antituberculous antibiotics are not necessary in the chronic phase but they may be helpful if ongoing inflammation or infection is present. Granulomatous prostatitis, epididymo-orchitis, ureteral obstruction and renal abscess can be considered as complications resulting from BCG contaminated urine. The induration associated with chronic granulomatous prostatitis cannot be distinguished by rectal examination from &arcinoma of the prostate. Granulomatous prostatitis is most often asymptomatic. Prostate specific antigen levels are often elevated and ultrasound typically shows diffuse hypoechoic areas. The diagnosis is then made by needle biopsy. In patients with symptoms of acute granulomatous prostatitis, for example urinary retention, 300 mg. isoniazid and 600 mg. rifampin orally are recommended for 3 to 6 months. This therapy is also advised in patients with epididymo-orchitis. In rare cases abscess or even fistula formation has been described. Orchiectomy rarely may be required. Ureteral obstruction is a serious complication of BCG therapy. Generally, obstruction is temporary and self-limiting after cessation of the therapy. Again, the combination of 300 mg. isoniazid and 600 mg. rifampin is prescribed for 3 to 6 months. Apart from this therapy temporary percutaneous drainage of the kidney may be necessary. Renal abscess has been reported in rare cases. Abscess formation is associated with vesicoureteral reflux. Although reflux per se is not a strict contraindication to intravesical BCG therapy, patients with reflux have an increased risk of pyelonephritis, renal abscess and ureteral obstruction. Many patients with unknown reflux have been treated with BCG, since cystograms are not routinely done nor necessarily advised before BCG therapy. Systemic side effects. Categorized as systemic side effects of BCG intravesical therapy are fever, influenza-like symptoms, malaise and chills, pneumonitis, hepatitis, rash, arthralgia and arthritis, renal abscess, ureteral obstruction, cytopenia and sepsis. Low grade fever (less than 38.5C) in combination with influenza-like symptoms, malaise and chills is encountered frequently. This combination of symptoms probably represents the immune response to BCG. Symptoms usually resolve spontaneously within 48 hours but antipyretic drugs are generally helpful. Antituberculous drugs are not necessary. However, it is not possible to distinguish patients with a simple uncomplicated reaction from those who will have progressive systemic infections or even sepsis. Therefore, careful monitoring is required in patients with fever of more than 38.5C. Fever of more than 39.5C that does not resolve within 12 hours despite antipyretic therapy is potentially dangerous. Definitive cessation of BCG therapy is recommended and isoniazid (300 mg. daily) should be administered for 3 months. Pyridoxine (25 to 50 mg. daily) is generally recommended for patients who are on long-term isoniazid. Skin rash, arthralgia and migratory
Treatment recommendations for ECG-related complications
Fever Greater Than 38.5C for 12-24 Hrs. Isoniazid at 300 mg. daily for 3 mos. May resume BCG when asymptomatic
Allergic Reactions
Acute Severe Illness
Sepsis
Isoniazid at 300 mg. daily for 3 mos. Further BCG is indicated only if benefit exceeds risk
Isoniazid at 300 mg., rifampin at 600 mg., ethambutol at 1,200 mg. daily for 6 mos., no further BCG
Isoniazid at 300 mg., rifampin at 600 mg., ethambutol at 1,200 mg., cycloserine at 500 mg. twice daily, consider prednisolone at 40 mg. intravenously and acutely
1NTRAVE:SICAL BACILLU-8 CALivlETTE-GUE:R,IN IN SUPERFICIAL BLADDER CANCER
arthritis are considered to be allergic reactions. If symptoms do not respond to treatment with antihistamines and anti-inflammatory agents, treatment with 300 mg. isoniazid orally for 3 months is usually sufficient for total recovery. Definitive cessation of BCG instillations is recommended. Systemic BCG infection manifested by granulomatous pneumonitis or hepatitis is a serious complication often resulting in severe illness and high fever. The diagnosis is made by chest xray and needle biopsy of the liver. Elevation of liver enzymes is usually present. Treatment consists of the isoniazid-rifampin combination therapy for 6 months. In acutely ill patients triple antituberculous therapy is recommended: 300 mg. isoniazid, 600 mg. rifampin and 1,200 mg. ethambutol daily for 6 months. BCG therapy should be permanently abandoned. Sepsis following intravesical BCG instillation is the most serious known complication and can be lethal. Although BCG is an attenuated strain of mycobacterium tuberculosis the decreased virulence and retained sensitivity to tuberculous drugs have not rendered it completely harmlesso The massive dose administered intravesically is a potential lethal dose when given intravenously, particularly in patients who have been previously immunized with BCG. The barrier normally preventing massive systemic spread from the bladder can be eliminated when there is a fresh bleeding wound in the urethra or bladder, or a severely inflamed urothelium. Since most cases of sepsis are associated with intravenous absorption of BCG it is recommended that BCG not be given until at least 1 week after tumor resectiono Patients present with all of the classical symptoms of sepsis, including circulatory collapse, acute respiratory distress and disseminated intravascular coagulopathy. BCG is generally highly sensitive to antituberculous drugs, including isoniazid, rifampin, para-aminosalicylic acid, streptomycin, ethambutol and to a lesser degree kanamycin and gentamicin. Mycobacterial infections resistant to 1 or more drugs have been reported. 20 Of all antituberculous drugs isoniazid is used most frequently. Although isoniazid usually is safe, it is occasionally associated with adverse reactions, the most significant of which is hepatitis. Elevation of serum transaminase activity occurs in 10 to 20% of the patients. 21 Enzyme levels return to normal in most persons despite continuation of medicationo Alcohol consumption may enhance the risk of isoniazid-associated hepatitis. If any of the liver function tests exceeds 3 to 5 times the upper limit of normal, discontinuation of isoniazid should be strongly considered. As in the treatment of tuberculosis, the use of steroids in the treatment of BCG reactions is somewhat controversial. The use of corticosteroids has risks but the demonstrated absence of organisms in many patients with diffuse granulomas suggests that reactions may be the result of type IV hypersensitivity reactions. The reported 100% survival in 5 patients with systemic BCG infection treated with isoniazid, rifampin and prednisolone, and our unpublished data showing that the LD50 of BCG in mice treated with BCG is less than 20% of that in unimmunized mice suggest that until further studies can be completed 40 mg. prednisolone per day should be given in addition to antituberculous antibiotics in patients with life-threatening BCG reactions. In vitro data suggest that the antituberculous drug cycloserine inhibits BCG growth within 24 hours. 22 Peak serum concentrations are achieved 3 to 4 hours after oral administration. Isoniazid, rifampin, ethambutol, streptomycin and para-aminosalicylic acid require 2 to 7 days to inhibit BCG growth. Therefore, cycloserine may be lifesaving in patients with BCG sepsis. We recommend treating these patients with isoniazid, rifampin and ethambutol plus 500 mg. cycloserine orally 2 times daily for 5 days. Considerations should also be given to the use of 40 mg. prednisolone daily, since shock secondary to hypersensitivity reaction cannot be distinguished from that due to overwhelming infection. At least 7 patients who apparently suffered from overwhelming systemic BCG infection have died.
599
In almost all cases these patients had traumatic catheterization before instillation therapy, or they were treated too early after transurethral prostatectomy or biopsy. To our knowledge no patient who has been treated with antituberculous antibiotics plus cycloserine or prednisolone has died. There is no information about possible immunological defects in this group. Fatalities have been observed after administration of the commonly used BCG preparations (Connaught, Tice, Pasteur and probably RIVM strains). This superiority of BCG immunotherapy for prophylaxis of superficial bladder cancer and therapy for carcinoma in situ has been established and has increased its use throughout the world. Adverse effects and severe complications are more marked than in chemotherapeutic instillation therapy. Therefore, patients with stage Ta, grade 1 tumors are not recommended as candidates for BCG unless they have failed prior chemotherapy. However, more than 95% of the patients tolerate BCG instillations well without any complication. With increased experience and knowledge the number and severity of adverse reactions should decrease. It is essential for general physicians and urologists to distinguish among normal therapyrelated symptoms, adverse effects and complications of this therapy. Immediate treatment of the complications with single or combination antituberculous therapy should result in complete recovery in virtually all patients. REFERENCES 1. Haff, K 0., Dresner, So M., Kelley, D. R., Ratliff, T. L., Shapiro,
A. and Catalona, W. J.: Role of immunotherapy in the prevention of recurrence and invasion of urothelial bladder tumors: a review. World J. Urol., 3: 76, 1985. 2. Brosman, So A.: Experience with bacillus Calmette-Guerin in patients with superficial bladder carcinomao J. Urol., 128: 27, 1982.
3. Steg, A., Leleu, C., Debre, B., Boccon-Gibod, L. and Sicard, D.: Systemic bacillus Calmette-Guerin infection in patients treated by intravesical BCG therapy for superficial bladder cancer. In: EORTC Genitourinary Group Monograph 6: BCG in Superficial Bladder Cancer. Edited by F. M. Jo Debruyne, L. Denis and A. Po M. van der Meijden. New York: Alan R. Liss, Inc., pp. 325334, 1989.
4. Lamm, D. L., Stogdill, Y D., Stogdill, B. J. and Crispen, R. G.: Complications of bacillus Calmette-Guerin immunotherapy in 1,278 patients with bladder cancer. J. Urol., 135: 272, 1986. 5. Kelley, D. R, Ratliff, T. L., Catalona, W. J., Shapiro, A., Lage, J.M., Bauer, WO C., Haaff, E. 0. and Dresner, S. M.: Intravesical bacillus Calmette-Guerin therapy for superficial bladder cancer: effect of bacillus Calmette-Guerin viability on treatment results. J. Urol., 134: 48, 1985. 6. Ratliff, T. L., Palmer, J. 0., McGarr, J. A. and Brown, E. J.: Intravesical bacillus Calmette-Guerin therapy for murine bladder tumors: initiation of the response by fibronectin-mediated attachment of bacillus Calmette-Guerino Cancer Res., 4 7: 1762, 1987.
7. van der Meijden, A. P. M., de Jong, W. H., Steerenberg, P. A., Walvoort, H. C., de Boer, E. C., Debruyne, F. Mo J. and Ruitenberg, E. J.: Intravesical BCG administration in the guinea pig. A histomorphological study. Virchows Arch., 55: 207, 1988. 8. Lage, J.M., Bauer, W. C., Kelley, D.R., Ratliff, T. L. and Catalana, W. J.: Histological parameters and pitfalls in the interpretation of bladder biopsies in bacillus Calmette-Guerin treatment of superficial bladder cancero J. Urol., 135: 916, 19860 9. Hunt, J. S., Silverstein, M. J., Sparks, F. C., Haskell, C. M., Pilch, Y. H. and Morton, D. L.: Granulomatous hepatitis: a complication of BCG immunotherapy. Lancet, 2: 820, 1973. 10. Bodurtha, A., Kim, Y. H., Laucius, J. F., Donato, R. A. and Mastrangelo, M. J.: Hepatic granulomas and other hepatic lesions associated with BCG immunotherapy for cancer. Amer. J. Clin. Path., 61: 747, 1974. 11. Sparks, F. C.: Hazards and complications of BCG immunotherapy. Med. Clin. North Amer., 60: 499, 1976. 12. Lotte, A., Wasz-Hiickert, 0., Poisson, N., Dumitrescu, N., Verron, M. and Couvet, E.: BCG complications. Estimates of the risks among vaccinated subjects and statistical analysis of their main characteristics. Adv. Tuberco Res., 21: 107, 1984.
600
LAMM AND ASSOCIATES
13. Schwarzenberg, L., Simmler, M. C. and Pico, J. L.: Human toxi-
18. Reichert, D. F. and Lamm, D. L.: Long term protection in bladder
cology of BCG applied in cancer immunotherapy. Cancer lmmunol. Immunother., 1: 69, 1976. 14. Lowe, J., Iles, P. B., Shore, D. F., Langman, M. J. S. and Baldwin, R. W.: Intrapleural BCG in operable lung cancer. Lancet, 1: 11,
cancer following intralesional immunotherapy. J. Urol., 132:
1980. 15. Whittaker, J. A., Bentley, D. P., Melville-Jones, G. R. and Slater,
A. J.: Granuloma formation in patients receiving BCG immunotherapy. J. Clin. Path., 29: 263, 1976. 16. Lamm, D. L., Sarosdy, M. S. and DeHaven, J. I.: Percutaneous, oral, or intravesical BCG administration: what is the optimal route? In: EORTC Genitourinary Group Monograph 6: BCG in Superficial Bladder Cancer. Edited by F. M. J. Debruyne, L. Denis and A. P. M. van der Meijden. New York: Alan R. Liss, Inc., pp. 301-310, 1989. 17. Bast,_R. C., Jr., Zhar, B., Borsos, T, and Rapp, H. J.: BC_G and cancer. New Engl. J. Med., 290: 1413, 1974.
570, 1984. 19. Brosman, S. A., Lamm, D. L., van der Meijden, A. P. M. and
Debruyne, F. M. J.: A practical guide to the use of intravesical BCG for the management of stage Ta, Tl, and CIS transitional cell cancer. In: EORTC Genitourinary Group Monograph 6: BCG in Superficial Bladder Cancer. Edited by F. M. J. Debruyne, L. Denis and A. P. M. van der Meijden. New York: Alan R. Liss, Inc., pp. 311-323, 1989. 20. Aungst, C. W., Sokal, J.E. and Jager, B. V.: Complications of BCG vaccination in neoplastic disease. Ann. Intern. Med., 82: 666, 1975.
21. Bass, J. B., Jr., Farer, L. S., Hopewell, P. C. and Jacobs, R. F.: Treatment of tuberculosis and tuberculosis infection in adults and childre11a_Amer. Rev. Re~gir~Dis., 134: 355,_11)8_6. 22. Lee, T. S. and Crispen, R. G.: Personal communication.
THE JOURNAL OF UROLOGY Copyright© 1992 by AMERICAN UROLOGICAL ASSOCIATION, INC.
Printed in U.S.A.
INCIDENCE AND TREATMENT OF COMPLICATIONS OF BACILLUS CALMETTE-GUERIN INTRAVESICAL THERAPY IN SUPERFICIAL BLADDER CANCER DONALD L. LAMM, AD P. M. VAN DER MEIJDEN, ALVARO MORALES, STANLEY A. BROSMAN, WILLIAM J. CATALONA, HARRY W. HERR, MARKS. SOLOWAY, ADOLPHE STEG AND FRANS M. J. DEBRUYNE From the Departments of Urology, West Virginia University School of Medicine, Morgantown, West Virginia; University Hospital Nijmegen, Nijmegen, The Netherlands; Queen's University Kingston, Kingston, Ontario, Canada; UCLA Center for Health Sciences, Los Angeles, California; Washington University School of Medicine, St. Louis, Missouri; Memorial Sloan-Kettering Cancer Center, New York, New York;University of Miami, Miami, Florida, and Hopital Cochin, Paris, France
ABSTRACT
Intravesical therapy with bacillus Calmette-Guerin (BCG) has proved to be more effective in the prophylaxis and treatment of superficial bladder tumors and carcinoma in situ than most chemotherapeutic agents. Compared to intravesical chemotherapy, instillations with BCG provoke more local and systemic reactions. In addition to the commonly induced granulomatous inflammatory changes in the bladder, which produce irritative symptoms, this therapy may cause systemic side effects varying from mild malaise and fever to, in rare instances, life-threatening or fatal sepsis. We report the incidence and varieties of toxicities in 2,602 patients treated with intravesical BCG. Side effects are classified according to local and systemic toxicity. Treatment options vary according to the severity of toxicity from delaying or withholding instillations to treatment with antituberculous drugs for up to 6 months. In general, 95% of the patients have no serious side effects. Recognition of risk factors, particularly traumatic catheterization or concurrent cystitis, that result in systemic BCG absorption, as well as the prompt and appropriate treatment of early side effects should significantly decrease the incidence of severe toxicity. KEY WORDS:
bladder neoplasms, BCG vaccine, carcinoma in situ
Intravesical instillations of bacillus Calmette-Guerin (BCG) have been shown to be effective treatment of and prophylaxis against recurrent stages Ta and Tl tumors and carcinoma in situ. A variety of treatment schedules, BCG preparations and doses have been used. 1 The optimal BCG preparation, treatment schedule and dose have not yet been identified. It is possible that optimal therapy differs from patient to patient as a result of tumor and host factors that also remain to be identified. Toxicity has been reported to be substantially greater with intensive regimens but severe side effects have also bee·n observed after only a few instillations. 2 • 3 In many series the reported toxicity of intravesical BCG therapy is greater than that of intravesical chemotherapy. However, prospective randomized comparisons of BCG and chemotherapy have demonstrated no substantial differences in local toxicity. Considering risk and benefit for the individual patient, BCG should not be administered to patients with low stage, low grade (stage pTa, grade 1) unifocal or primary tumors. The risk for tumor recurrence or progression is low in these tumor categories. The majority of patients tolerate BCG instillations well but adverse effects can and do occur. While systemic complications of BCG are uncommon their variety and potential severity demand our attention. We document the incidence of BCGinduced side effects and serious complications, and devise a rational approach to their diagnosis and management. We update our previous series reported in 1986 in which cystitis occurred in 91 % of the patients, hematuria in 43%, low grade fever in 28%, malaise in 24% and nausea in 8%. Fever of more than 39.5C was observed in 3.9% of the patients, granulomatous prostatitis in 1.3%, granulomatous pneumonitis or hepatitis in 0.9%, arthritis or arthralgia in 0.5%, epididymo-orchitis in 0.2%, bladder contracture in 0.2%, hypotension in 0.1% and Accepted for publication July 12, 1991.
cytopenia in 0.1 %. There were differences in the frequency of complications using various BCG preparations (Armand Frappier, Tice, Connaught and Pasteur strains). Some of these differences, however, reflect variations in dose and treatment schedule as well as differences in judgment regarding the severity of adverse effects among the individual urologists. MATERIALS AND METHODS
We expand a review of 1,278 patients reported on in 1986 in which the reactions are described among 1,324 patients treated by multiple investigators in Canada, the United States and Europe. 4 The initial review tabulated both series and detailed questionnaires from major investigators at the time. The current review updates and expands the previous review by adding the results of our series as reported by the European Organization for Research on Treatment of Cancer Genitourinary Group. In addition, treatment recommendations are the result of a consensus meeting of the authors held during the 1989 meeting of the American Urological Association. RESULTS
With the expansion of this experience to a total of 2,602 patients treated with the Armand Frappier, Tice, Connaught, Pasteur or RIVM strain of BCG, no significant change in the complication rate was observed. High fever (greater than 39C) was noted in 2.9% of the patients. Histologically documented granulomatous prostatitis decreased from an incidence of 1.3 to 0.9%. Major hematuria occurred in 1.0% of the patients. Granulomatous pneumonitis and/or hepatitis as a result of systemic BCG infection was observed in 0.7% of the patients, while life-threatening BCG sepsis was noted in 0.4%, arthritis and arthralgia occurred in 0.5% and skin rash in 0.3%. The incidence of ureteral obstruction (0.3 %), epididymo-orchitis (0.4%) and bladder contracture (0.2%) remained essentially
596
597
INTRAVESJ:CAL BACILLUS CALMETTE-GUERIN IN SUPERFICIAL BLADDER CANCER
unchanged. The incidence of complications in 2,602 patients is shown in table 1. DISCUSSION
BCG is the attenuated strain of the bovine tuberculous bacterium and consists of living bacilli, dead microorganisms and subcellular debris. It maintains the immunological properties and antibiotic sensitivities of the parent strain. Variability in the dose and viability can be expected among the different suppliers of BCG and even among different lots from the same supplier. 5 Storage of the vials at the correct temperature is critical for the survival of the mycobacteria. Apart from possible differences in efficacy and toxicity between the different BCG preparations it is difficult to distinguish between therapyrelated symptoms that may indicate efficacy and symptoms that may represent adverse effects. Therefore, it is sometimes difficult to define the true toxicity of this therapy. Many investigators believe that an inflammatory reaction is an important component of the response to BCG therapy. The attachment of BCG bacilli to the damaged bladder wall has been clearly demonstrated. 6 Following attachment, histological examination of the bladder mucosa reveals granulomatous inflammatory reactions and mononuclear cell infiltration predominantly in the subepithelial layer of the bladder wall. 7•8 Granulomas are commonly found in the bladder wall and also can be found in the primary draining lymph nodes of the bladder, and on rare occasions throughout the liver and lungs. It is most unusual to detect BCG microorganisms in these granulomas. 7 Granulomatous hepatitis has been reported in cancer patients after intralesional and intradermal BCG administration. Such reactions appear to be hypersensitivity responses, since viable mycobacteria have not been recovered from these lesions. 9 ' 10 Therefore, many believe that granulomas outside the primary inoculated site are the results of hypersensitivity reactions to BCG antigens. Toxic side effects that occur after BCG immunotherapy in cancer patients can be divided into local and systemic categories. Important factors for this toxicity are the route of administration, number of repeated injections and dose of BCG. The local side effects of BCG skin inoculations are well known from the extensive experience with the BCG vaccine for prevention of tuberculosis. 11 Complications from vaccination are manifested by persistence of ulceration, localized abscess formation, granuloma formation or regional lymphadenitis. Systemic complications and generalized BCG infection have been reported, especially in children with immunodeficiency syndromes. A total of 35 fatalities has been reported among more than 1.5 billion vaccinations for tuberculosis prophylaxis, 12 Almost all of these fatalities occurred in children with defects in cellular immunity. Complications of BCG vaccination in cancer therapy are relatively rare but are more frequent than in tuberculosis vaccination programs. This is probably related to the impaired TABLE 1.
Fever Granulomatous prostatitis Pneumonitis/hepatitis Arthralgia Hematuria Rash U reteral obstruction Epididymitis Contracted bladder Renal abscess Sepsis Cytopenia
immunological status of many cancer patients and to the intralesional application of BCG. In some instances intralesional administration might be equivalent to intravenous injection, since tumor nodules may be highly vascularized. 13 Fever of 40C, severe malaise, hepatic dysfunction and granuloma formation in the liver and lungs have been described after intralesional BCG injection. BCG has been administered intrapleurally for adjuvant treatment of lung cancer. Severe side effects of this therapy were observed on rare occasion and were mostly related to high doses of BCG. However, hepatic dysfunction and weight loss were reported more frequently. 14 After orally administered BCG no toxicity was observed. When viable BCG is injected intravenously severe toxicity can be encountered. Granuloma formation was observed in bone marrow, liver, lungs, spleen and lymph nodes in cancer patients treated by intravenous administration. 15 Thousands of patients with superficial bladder cancer including carcinoma in situ have been treated with BCG. Intravesical instillation has proved to be the most effective route of administration.16 The complications encountered are more frequent and more severe than those seen with vaccination for tuberculosis. Although less frequent, complications seen after intravesical instillation are comparable to those observed after intralesional injection. The symptoms, histological appearance and localization of granulomas are similar. While only 1 death per 50 million patients occurred if BCG was given for tuberculosis prophylaxis, a mortality rate of l death per 12,500 patients was observed when BCG was administered in the treatment of cancer patients. In the patients with superficial bladder cancer treated intravesically with BCG at least 7 deaths have been associated with although not conclusively caused by its use. It is unknown how many patients have been treated with BCG intravesically because not all patients are enrolled in trials. While the mortality rate in bladder cancer patients treated with intravesical BCG cannot be accurately estimated to date, it is anticipated that it will be less than l death per 12,500 patients, since intralesional injection results in intravenous absorption of BCG more frequently than topical application and, unlike many patients with other malignancies, patients with superficial bladder cancer generally have an intact immune system. Contraindications in ECG use. Intravesical BCG immunotherapy should not be used in patients suffering from active tuberculosis and it should be used with great caution, if at all, in patients with congenital or acquired immunodeficiency syndromes (AIDS), leukemia or Hodgkin's disease. Transplant recipients and patients with positive human immunodeficiency virus serology with or without clinical manifestations of AIDS should also not be treated with BCG. Finally, BCG should be avoided during pregnancy and lactation, and in cases of intractable urinary tract infection. Although sexual transmission of BCG has not been reported it has been suggested that a condom should be used during coitus for 1 week after BCG therapy. The adverse effects of intravesical BCG therapy could be clas-
Complications in 2,602 patients according to substrains of BCG
Total No.(%) (2,602 pts.)
% Armand Frappier (718 pts.)
% Tice (726 pts.)
% Connaught (353 pts.)
% Pasteur (325 pts.)
%RIVM (129 pts.)
75 (2.9) 23 (0.9)
3.8
4.7
1.8
18 (0.7)
0.4 0.7 0.3 0.4 0.6 0.4
1.0 0,8
4.7 0.2 0.6 0.6 2.4
0,6 0.6 1.2
1.8
2.1 0.0 0.8 0.0
1.0
0.4
0.9
0.0
0.2 0.2 0.2 0.4
0.0 1.2 0,6
0.0 0.0 0.8
0.0
0.0
0.9 0.0
0.2 0.0
0.0
12 (0.5) 24 (1.0) 8 (0.3) 8 (0.3) 10 (0.4) 6 (0.2) 2 (0.1) 10 (0.4) 2 (0.1)
0.0 0.0 0.1 0.0
0.1 0.6 0.0 0.4
0.0 0.3 0.0 0.4 0.3
0.0 0.0
Since definitions of side effects differ from one series to another and all complications were not considered in each series, some asumptions have been made to estimate the overall incidence of complications.
598
LAMM AND ASSOCIATES
sified as local or systemic, and subdivided into minor and major toxicity groups according to treatment considerations. Our suggested treatment of ECG-related complications is summarized in table 2. Local side effects. Local side effects of BCG instillation therapy are defined as effects confined to the bladder or those organs that are in contact with BCG bacilli. Reported side effects include bacterial cystitis (not ECG-related), drug-induced or chemical cystitis, minor and major hematuria, bladder contracture, granulomatous prostatitis, epididymo-orchitis, ureteral obstruction and renal abscess. Culture proved bacterial cystitis not specifically related to BCG is treated with antibiotics until the culture becomes negative and symptoms have resolved. We recommend withholding BCG instillations during treatment of bacterial urinary tract-infections for 2 reasons: 1) the combination of bacterial cystitis and drug-induced (BCG) cystitis can cause severe inflammatory reactions that may lead to more side effects and 2) BCG bacilli are sensitive to antibiotic therapy and a decrease in antitumor efficacy may occur. In vitro culture experiments indicate that BCG microorganisms can be eradicated by a number of antibiotics, including trimethoprim sulfamethoxazole and norfloxacin (unpublished observations). It is logical to expect that concomitant administration of antituberculous drugs would diminish the antitumor effects of BCG but animal studies have demonstrated that concomitant isoniazid therapy does not decrease the antitumor efficacy. Moreover, animal studies have clearly demonstrated that administration of excessive doses of BCG results in diminished antitumor immunity. 17• 18 Since BCG is a living organism that can survive and multiply after intravesical instillation, patients with persistent symptoms should be treated not only to prevent side effects but also to prevent a decrease in antitumor immune responses. Cystitis caused by BCG is defined as drug-induced or BCG cystitis. Drug-induced cystitis typically consists on biopsy of acute and chronic inflammation with or without granuloma formation. Patients complain of urinary frequency, urgency and pain in the bladder region. Repeated BCG administration increases the incidence and severity of cystitis. The normal bacterial urine culture remains negative. Symptoms generally start 2 to 4 hours after instillation and will typically subside without therapy within 6 to 48 hours. Relief is produced by symptomatic medication, such as phenazopyridine, propantheline bromide or oxybutynin. Drug-induced cystitis is considered by most investigators as a normal reaction to BCG therapy. In fact, when some degree of cystitis does not occur there is reason to question the adequacy of the treatment. 19 Antituberculous drugs, such as isoniazid, are not generally necessary. Postponement of instillation is advised until symptoms from the previous instillation have completely resolved. Hematuria is another local side effect often associated with drug-induced cystitis. Only on rare occasions is hematuria sufficient to require catheterization or transfusion. Hematuria is often observed after large tumor resections or in the presence of unresected friable tumors. Bladder contracture is a serious local complication. It has been observed predominantly in patients treated on a maintenance schedule but it also has been reported after multiple TABLE 2.
Fever Less Than 38.5C No treatment Hold BCG until symptoms have resolved
transurethral resections and instillations with chemotherapeutic drugs. Because of the low frequency (0.2%) of contracted bladder, and the pretreatment of most patients with multiple transurethral resections and other drugs it is difficult to state with certainty whether BCG alone causes bladder contracture. Treatment of this problem consists of withholding BCG, hydrodistension and sometimes bladder augmentation. Antituberculous antibiotics are not necessary in the chronic phase but they may be helpful if ongoing inflammation or infection is present. Granulomatous prostatitis, epididymo-orchitis, ureteral obstruction and renal abscess can be considered as complications resulting from BCG contaminated urine. The induration associated with chronic granulomatous prostatitis cannot be distinguished by rectal examination from &arcinoma of the prostate. Granulomatous prostatitis is most often asymptomatic. Prostate specific antigen levels are often elevated and ultrasound typically shows diffuse hypoechoic areas. The diagnosis is then made by needle biopsy. In patients with symptoms of acute granulomatous prostatitis, for example urinary retention, 300 mg. isoniazid and 600 mg. rifampin orally are recommended for 3 to 6 months. This therapy is also advised in patients with epididymo-orchitis. In rare cases abscess or even fistula formation has been described. Orchiectomy rarely may be required. Ureteral obstruction is a serious complication of BCG therapy. Generally, obstruction is temporary and self-limiting after cessation of the therapy. Again, the combination of 300 mg. isoniazid and 600 mg. rifampin is prescribed for 3 to 6 months. Apart from this therapy temporary percutaneous drainage of the kidney may be necessary. Renal abscess has been reported in rare cases. Abscess formation is associated with vesicoureteral reflux. Although reflux per se is not a strict contraindication to intravesical BCG therapy, patients with reflux have an increased risk of pyelonephritis, renal abscess and ureteral obstruction. Many patients with unknown reflux have been treated with BCG, since cystograms are not routinely done nor necessarily advised before BCG therapy. Systemic side effects. Categorized as systemic side effects of BCG intravesical therapy are fever, influenza-like symptoms, malaise and chills, pneumonitis, hepatitis, rash, arthralgia and arthritis, renal abscess, ureteral obstruction, cytopenia and sepsis. Low grade fever (less than 38.5C) in combination with influenza-like symptoms, malaise and chills is encountered frequently. This combination of symptoms probably represents the immune response to BCG. Symptoms usually resolve spontaneously within 48 hours but antipyretic drugs are generally helpful. Antituberculous drugs are not necessary. However, it is not possible to distinguish patients with a simple uncomplicated reaction from those who will have progressive systemic infections or even sepsis. Therefore, careful monitoring is required in patients with fever of more than 38.5C. Fever of more than 39.5C that does not resolve within 12 hours despite antipyretic therapy is potentially dangerous. Definitive cessation of BCG therapy is recommended and isoniazid (300 mg. daily) should be administered for 3 months. Pyridoxine (25 to 50 mg. daily) is generally recommended for patients who are on long-term isoniazid. Skin rash, arthralgia and migratory
Treatment recommendations for ECG-related complications
Fever Greater Than 38.5C for 12-24 Hrs. Isoniazid at 300 mg. daily for 3 mos. May resume BCG when asymptomatic
Allergic Reactions
Acute Severe Illness
Sepsis
Isoniazid at 300 mg. daily for 3 mos. Further BCG is indicated only if benefit exceeds risk
Isoniazid at 300 mg., rifampin at 600 mg., ethambutol at 1,200 mg. daily for 6 mos., no further BCG
Isoniazid at 300 mg., rifampin at 600 mg., ethambutol at 1,200 mg., cycloserine at 500 mg. twice daily, consider prednisolone at 40 mg. intravenously and acutely
1NTRAVE:SICAL BACILLU-8 CALivlETTE-GUE:R,IN IN SUPERFICIAL BLADDER CANCER
arthritis are considered to be allergic reactions. If symptoms do not respond to treatment with antihistamines and anti-inflammatory agents, treatment with 300 mg. isoniazid orally for 3 months is usually sufficient for total recovery. Definitive cessation of BCG instillations is recommended. Systemic BCG infection manifested by granulomatous pneumonitis or hepatitis is a serious complication often resulting in severe illness and high fever. The diagnosis is made by chest xray and needle biopsy of the liver. Elevation of liver enzymes is usually present. Treatment consists of the isoniazid-rifampin combination therapy for 6 months. In acutely ill patients triple antituberculous therapy is recommended: 300 mg. isoniazid, 600 mg. rifampin and 1,200 mg. ethambutol daily for 6 months. BCG therapy should be permanently abandoned. Sepsis following intravesical BCG instillation is the most serious known complication and can be lethal. Although BCG is an attenuated strain of mycobacterium tuberculosis the decreased virulence and retained sensitivity to tuberculous drugs have not rendered it completely harmlesso The massive dose administered intravesically is a potential lethal dose when given intravenously, particularly in patients who have been previously immunized with BCG. The barrier normally preventing massive systemic spread from the bladder can be eliminated when there is a fresh bleeding wound in the urethra or bladder, or a severely inflamed urothelium. Since most cases of sepsis are associated with intravenous absorption of BCG it is recommended that BCG not be given until at least 1 week after tumor resectiono Patients present with all of the classical symptoms of sepsis, including circulatory collapse, acute respiratory distress and disseminated intravascular coagulopathy. BCG is generally highly sensitive to antituberculous drugs, including isoniazid, rifampin, para-aminosalicylic acid, streptomycin, ethambutol and to a lesser degree kanamycin and gentamicin. Mycobacterial infections resistant to 1 or more drugs have been reported. 20 Of all antituberculous drugs isoniazid is used most frequently. Although isoniazid usually is safe, it is occasionally associated with adverse reactions, the most significant of which is hepatitis. Elevation of serum transaminase activity occurs in 10 to 20% of the patients. 21 Enzyme levels return to normal in most persons despite continuation of medicationo Alcohol consumption may enhance the risk of isoniazid-associated hepatitis. If any of the liver function tests exceeds 3 to 5 times the upper limit of normal, discontinuation of isoniazid should be strongly considered. As in the treatment of tuberculosis, the use of steroids in the treatment of BCG reactions is somewhat controversial. The use of corticosteroids has risks but the demonstrated absence of organisms in many patients with diffuse granulomas suggests that reactions may be the result of type IV hypersensitivity reactions. The reported 100% survival in 5 patients with systemic BCG infection treated with isoniazid, rifampin and prednisolone, and our unpublished data showing that the LD50 of BCG in mice treated with BCG is less than 20% of that in unimmunized mice suggest that until further studies can be completed 40 mg. prednisolone per day should be given in addition to antituberculous antibiotics in patients with life-threatening BCG reactions. In vitro data suggest that the antituberculous drug cycloserine inhibits BCG growth within 24 hours. 22 Peak serum concentrations are achieved 3 to 4 hours after oral administration. Isoniazid, rifampin, ethambutol, streptomycin and para-aminosalicylic acid require 2 to 7 days to inhibit BCG growth. Therefore, cycloserine may be lifesaving in patients with BCG sepsis. We recommend treating these patients with isoniazid, rifampin and ethambutol plus 500 mg. cycloserine orally 2 times daily for 5 days. Considerations should also be given to the use of 40 mg. prednisolone daily, since shock secondary to hypersensitivity reaction cannot be distinguished from that due to overwhelming infection. At least 7 patients who apparently suffered from overwhelming systemic BCG infection have died.
599
In almost all cases these patients had traumatic catheterization before instillation therapy, or they were treated too early after transurethral prostatectomy or biopsy. To our knowledge no patient who has been treated with antituberculous antibiotics plus cycloserine or prednisolone has died. There is no information about possible immunological defects in this group. Fatalities have been observed after administration of the commonly used BCG preparations (Connaught, Tice, Pasteur and probably RIVM strains). This superiority of BCG immunotherapy for prophylaxis of superficial bladder cancer and therapy for carcinoma in situ has been established and has increased its use throughout the world. Adverse effects and severe complications are more marked than in chemotherapeutic instillation therapy. Therefore, patients with stage Ta, grade 1 tumors are not recommended as candidates for BCG unless they have failed prior chemotherapy. However, more than 95% of the patients tolerate BCG instillations well without any complication. With increased experience and knowledge the number and severity of adverse reactions should decrease. It is essential for general physicians and urologists to distinguish among normal therapyrelated symptoms, adverse effects and complications of this therapy. Immediate treatment of the complications with single or combination antituberculous therapy should result in complete recovery in virtually all patients. REFERENCES 1. Haff, K 0., Dresner, So M., Kelley, D. R., Ratliff, T. L., Shapiro,
A. and Catalona, W. J.: Role of immunotherapy in the prevention of recurrence and invasion of urothelial bladder tumors: a review. World J. Urol., 3: 76, 1985. 2. Brosman, So A.: Experience with bacillus Calmette-Guerin in patients with superficial bladder carcinomao J. Urol., 128: 27, 1982.
3. Steg, A., Leleu, C., Debre, B., Boccon-Gibod, L. and Sicard, D.: Systemic bacillus Calmette-Guerin infection in patients treated by intravesical BCG therapy for superficial bladder cancer. In: EORTC Genitourinary Group Monograph 6: BCG in Superficial Bladder Cancer. Edited by F. M. Jo Debruyne, L. Denis and A. Po M. van der Meijden. New York: Alan R. Liss, Inc., pp. 325334, 1989.
4. Lamm, D. L., Stogdill, Y D., Stogdill, B. J. and Crispen, R. G.: Complications of bacillus Calmette-Guerin immunotherapy in 1,278 patients with bladder cancer. J. Urol., 135: 272, 1986. 5. Kelley, D. R, Ratliff, T. L., Catalona, W. J., Shapiro, A., Lage, J.M., Bauer, WO C., Haaff, E. 0. and Dresner, S. M.: Intravesical bacillus Calmette-Guerin therapy for superficial bladder cancer: effect of bacillus Calmette-Guerin viability on treatment results. J. Urol., 134: 48, 1985. 6. Ratliff, T. L., Palmer, J. 0., McGarr, J. A. and Brown, E. J.: Intravesical bacillus Calmette-Guerin therapy for murine bladder tumors: initiation of the response by fibronectin-mediated attachment of bacillus Calmette-Guerino Cancer Res., 4 7: 1762, 1987.
7. van der Meijden, A. P. M., de Jong, W. H., Steerenberg, P. A., Walvoort, H. C., de Boer, E. C., Debruyne, F. Mo J. and Ruitenberg, E. J.: Intravesical BCG administration in the guinea pig. A histomorphological study. Virchows Arch., 55: 207, 1988. 8. Lage, J.M., Bauer, W. C., Kelley, D.R., Ratliff, T. L. and Catalana, W. J.: Histological parameters and pitfalls in the interpretation of bladder biopsies in bacillus Calmette-Guerin treatment of superficial bladder cancero J. Urol., 135: 916, 19860 9. Hunt, J. S., Silverstein, M. J., Sparks, F. C., Haskell, C. M., Pilch, Y. H. and Morton, D. L.: Granulomatous hepatitis: a complication of BCG immunotherapy. Lancet, 2: 820, 1973. 10. Bodurtha, A., Kim, Y. H., Laucius, J. F., Donato, R. A. and Mastrangelo, M. J.: Hepatic granulomas and other hepatic lesions associated with BCG immunotherapy for cancer. Amer. J. Clin. Path., 61: 747, 1974. 11. Sparks, F. C.: Hazards and complications of BCG immunotherapy. Med. Clin. North Amer., 60: 499, 1976. 12. Lotte, A., Wasz-Hiickert, 0., Poisson, N., Dumitrescu, N., Verron, M. and Couvet, E.: BCG complications. Estimates of the risks among vaccinated subjects and statistical analysis of their main characteristics. Adv. Tuberco Res., 21: 107, 1984.
600
LAMM AND ASSOCIATES
13. Schwarzenberg, L., Simmler, M. C. and Pico, J. L.: Human toxi-
18. Reichert, D. F. and Lamm, D. L.: Long term protection in bladder
cology of BCG applied in cancer immunotherapy. Cancer lmmunol. Immunother., 1: 69, 1976. 14. Lowe, J., Iles, P. B., Shore, D. F., Langman, M. J. S. and Baldwin, R. W.: Intrapleural BCG in operable lung cancer. Lancet, 1: 11,
cancer following intralesional immunotherapy. J. Urol., 132:
1980. 15. Whittaker, J. A., Bentley, D. P., Melville-Jones, G. R. and Slater,
A. J.: Granuloma formation in patients receiving BCG immunotherapy. J. Clin. Path., 29: 263, 1976. 16. Lamm, D. L., Sarosdy, M. S. and DeHaven, J. I.: Percutaneous, oral, or intravesical BCG administration: what is the optimal route? In: EORTC Genitourinary Group Monograph 6: BCG in Superficial Bladder Cancer. Edited by F. M. J. Debruyne, L. Denis and A. P. M. van der Meijden. New York: Alan R. Liss, Inc., pp. 301-310, 1989. 17. Bast,_R. C., Jr., Zhar, B., Borsos, T, and Rapp, H. J.: BC_G and cancer. New Engl. J. Med., 290: 1413, 1974.
570, 1984. 19. Brosman, S. A., Lamm, D. L., van der Meijden, A. P. M. and
Debruyne, F. M. J.: A practical guide to the use of intravesical BCG for the management of stage Ta, Tl, and CIS transitional cell cancer. In: EORTC Genitourinary Group Monograph 6: BCG in Superficial Bladder Cancer. Edited by F. M. J. Debruyne, L. Denis and A. P. M. van der Meijden. New York: Alan R. Liss, Inc., pp. 311-323, 1989. 20. Aungst, C. W., Sokal, J.E. and Jager, B. V.: Complications of BCG vaccination in neoplastic disease. Ann. Intern. Med., 82: 666, 1975.
21. Bass, J. B., Jr., Farer, L. S., Hopewell, P. C. and Jacobs, R. F.: Treatment of tuberculosis and tuberculosis infection in adults and childre11a_Amer. Rev. Re~gir~Dis., 134: 355,_11)8_6. 22. Lee, T. S. and Crispen, R. G.: Personal communication.
