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Bacillus Calmette-Guerin in the Management of Bladder Cancer
0022-534 7/86/1352-0331$02.00/0 Vol. 135, February
THE JOURNAL OF UROLOGY
Copyright© 1986 by The Williams & Wilkins Co.
Printed in U.S.A.
Editorial BACILLUS CALMETTE-GUERIN IN THE MANAGEMENT OF BLADDER CANCER When the therapeutic effects of BCG were first reported Although bacillus Calmette-Guerin (BCG) long had been proposed for the treatment of cancer few expected as dramatic some suggested that the nonspecific inflammatory response an impact to be made as ultimately occurred when Morales and that resulted led to a generalized sloughing of cells, which associates first published their initial results on the use of BCG resulted in the elimination of neoplastic or preneoplastic cells in bladder cancer in 1976. 1 However, the articles in this issue as a bystander effect of the treatment. Early efforts to delineate of the Journal, as well as several others in recent issues, 2- 6 an immunological mechanism for the prophylactic effects that attest not only to the interest that was generated at that time were seen were unsuccessful,8 thereby indirectly confirming the but also to the astounding results that have been obtained. In nonspecific and possibly nonimmunological nature of BCG retrospect, perhaps this should not have been so surprising. treatment effectiveness. On the other hand, prophylactic and therapeutic success Results in experimental animal models had demonstrated that BCG would be effective against tumors if inoculated in close appeared to correlate with conversion of purified protein derivproximity to the tumor (direct contact), in appropriate dosage ative skin test responsiveness from negative to positive, 6 • 9 • 10 and in association with induction of an inflammatory (?immune implying that a systemic host reaction to intravesical instillaor hypersensitivity) response. 7 It was apparent from the original tion might either be a concomitant or a necessity for the work of Morales and associates that topical instillation of BCG therapeutic efficacy of BCG to be expressed. This concept was fulfilled all of these requirements. Moreover, numerous subse- supported further by observations that the number of viable quent reports documented the apparent efficacy of BCG instil- organisms actually inoculated into the bladder determined lation in the prevention of recurrent superficial bladder tumors whether prophylactic and therapeutic efficacy was achieved. 6 and effectively promoted this old therapeutic modality as a new Other reports describing prophylactic efficacy following oral and possibly more effective alternative to standard chemother- treatment with BCG5 and in some instances therapeutic effiapeutic prophylactic management of recurrent superficial blad- cacy for muscle-invasive bladder cancers on intravesical instillation of this agent11 • 12 further supported the hypothesis that der cancer. Not unexpectedly, therefore, was the excitement generated the induction of an immunological response (?hypersensitivity in the possible use of this agent in actual therapy as well. We reaction implicating T lymphocyte/macrophage stimulation are now beginning to see the initial results of studies reflecting and activation) might, indeed, be operative in the use of this this new and seemingly well founded interest. In a recent issue modality. Corresponding descriptions of a 77 per cent response of the Journal apparent successful therapy of residual tumor free of tumor in those bladders with a granulomatous reaction was documented in 54 per cent of the patients with a single compared with only a 32 per cent response in those lacking a BCG treatment and in an additional 2 of 5 initial failures granulomatous reaction6 confirmed earlier suggestions that this following a second course ofBCG. 6 In addition, complete regres- might be an important index of predicability of response, 1 • 13 as sion of carcinoma in situ was seen in 50 per cent of the patients, well as of the more deep-seated reaction necessary for satisfacand 3 of 5 with recurrent carcinoma in situ responded to a tory effectiveness to be achieved. Although some have observed second course ofBCG. 6 Similar treatment results for carcinoma that a granulomatous reaction to BCG can occur in the absence in situ were reported by Brosman, who suggested that two- of a delayed hypersensitivity response, 14 the cogency of evidence thirds of the patients responded to a 12-week course of therapy, remains in support of the concept that the systemic response while the 9 who did not respond initially were eventually to BCG instillation may be responsible, at least in part, for the rendered free of tumor following a 24-week course of therapy. 2 therapeutic response observed. Despite disclaimers by Kelley A similar therapeutic effect of BCG instillation (as contrasted and associates (page 268) that systemic responsiveness to BCG with a prophylactic effect) is confirmed by reports in this issue does not necessarily predict response to therapy, the correlation of the Journal. Schellhammer and associates (page 261) de- between apparent immune responsiveness to BCG and treatscribe a complete response in 71 per cent of the patients who ment results strongly suggests that systemic hypersensitivity had residual tumor after incomplete resection or with positive effects may hold a clue to the mechanism of action by BCG. selected site biopsies and/or post-resection positive cytology. Whether this mechanism is manifested by the simple sloughing Herr and associates (page 265) report that 68 per cent of 47 of the urothelium (and the bystander sloughing of neoplastic patients were free of carcinoma in situ (negative urine cytology, cells) as part of an inflammatory response possibly represented cystoscopy and biopsy) after a single 6-week course of intraves- by regional nonimmune granuloma formation, 15 or whether ical BCG therapy during a 4-year followup. These results appear there is an immune-inducing activity as represented by immune to extend the efficacy of BCG to a dramatic extreme if, in fact, granuloma formation with as yet poorly defined specificity for diffuse carcinoma in situ with its known progressive malignant tumor cells in the bladder remains to be determined. Perhaps basic to each of these possibilities is the role of potential can be eliminated successfully after such a short and various immunomodulatory proteins or cytokines that may be generally well tolerated course of relatively benign therapy. However, there clearly are many questions that remain un- produced in response to BCG. Most prominent among these is answered. Most prominent among these is the mechanism by the so-called tumor necrosis factor (TNF), a substance or which BCG exerts so profound a prophylactic/therapeutic ef- substances originally found to be produced in response to fect and the means by which this mechanism may interact with sequential treatment of mice with BCG and endotoxin. 16 TNFthe potential intrinsic behavior of a particular form of superfi- induced necrosis of implanted tumors in experimental animals with involvement of macrophages and lymphocytes, 17• 18 and cial (or in situ) bladder cancer. 331
332
DROLLER
possible synergism of cytotoxicity With interferon as produced under similar circumstances 19 may be analogous and especially applicable to the clinical situation presented by bladder cancer and its apparent response to BCG. These possibilities merit further investigation. The interaction of the response to BCG with the intrinsic biological behavior of a particular neoplasm is equally as intriguing because of the mystery it presents. This appears to be especially striking in the case of carcinoma in situ. Whereas 75 per cent of the patients with diffuse carcinoma in situ (20 to 30 per cent of whom already have microscopic penetration of tumor into the lamina propria) have traditionally been expected to have progressive bladder cancer and require cystectomy, 20 it would appear from the present reports of Schellhammer and Herr and their associates as well as earlier studies2• 6 that many of these patients can be rid of the disease after a single course of BCG, and that the majority can be cured upon extension of this course. If urothelial sloughing as the result of direct contact with an inflammatory reaction to BCG is responsible for its therapeutic efficacy, this may not be an entirely surprising result with in situ involvement of the bladder. However, it is a surprising result for those patients in whom the prostatic urothelium has been involved by in situ disease. This is especially true in those patients who have not undergone resection of the prostate and in whom direct contact of BCG with the site of tumor might be questioned. In those instances therapeutic response may reflect a systemic effect of BCG but it also may reflect the possibility of reflux of ECG-containing urine into the prostatic ducts during micturition. Findings of granlilomatous prostatitis reported by Lamm and associates (page 272) in a number of patients undergoing BCG instillation are compatibie with both possibilities, although in each case one might have expected to find this as a more common occutrence, given the apparent number of therapeutic responses that have been reported. Notwithstanding these encouraging findings, there are several important caveats that must be considered.. The first is that an interpretation of many of the apparently successful results presently being reported may actually be dependent upon whether the diagnosis of the carcinoma in situ lesion is real. Since accurate diagnosis of this lesion often is based entirely on interpretation of urinary cytology and interpretation of urinary cytology currently is an area of major controversy with varying agreement among expert pathologists, it is questionable whether the diagnosis of this lesion can truly be made with the consistency and uniformity that are necessary to assess these results. Furthermore, might it not be possible that pathologists have been more likely in recent years to diagnose cancer cells when they assumed that this wouid result in a course of BCG instillation? This would be consistent with what was seen in previous years when pathologists were reluctant to make a diagnosis of carcinoma in situ when they thought that this would lead to cystectomy. That infiltration of cancer in prostatic ducts may make such cancer inaccessible to topical BCG therapy also is a critical consideration. Since microscopic stromal infiitration often may be seen in these areas when additional sections are examined, such patients may be at serious risk of cancer progression despite apparent superficial control as diagnosed endoscopically or cytologically. it also may turn out that different forms of superficial cancer or carcinoma in situ may have varying susceptibility to BCG treatment. Presently, such variability is unpredictable. Indeed, progressive disease has been documented in our patients as well as those of Kelley and associates6 treated with BCG in whom significant prostatic involvement was found and persisted despite intensive therapy, and in others reported on by Herr and associates in whom muscle-infiltrating tumor also was found at variable intervals after initiation of BCG treatment for "superficial" tumor or carcinoma in situ. These obser-
vations, not unlike previous results with other forms of intravesical therapy for superficial bladder tumors or carcinoma in situ, 21 • 22 highlight the unpredicability of many of the lesions being treated and underscore the need to identify more clearly prognostic factors that may permit suitable intensive therapy for those patients likely to respond and more radical surgical therapy for those who remain at serious risk from the disease. Taken together, we may be at the forefront of a major change in our ability to manage bladder cancer. Certainly, BCG therapy as reported by Lamm and associates in multiple centers is safe in most patients. If, indeed, BCG has a systemic effect and if there is something unique about the transitional epithelium that allows an immune or an inflammatory response to BCG stimulation to eradicate successfully not only superficial disease in the bladder but also infiltrative disease in the bladder and in the prostatic urethra as well, then might it ultimately not be conceivable to apply such therapy even to those patients with more advanced regional bladder cancer in combination with one of the current systemic chemotherapy protocols to eradicate clinically apparent and/or subclinical metastatic disease? The painting of such an optimistic picture obviously is premature and must be shaded by consideration of the aforementioned caveats. Nonetheless, the results reported in this issue of the Journal and in previous issues may well represent a valid stimulus for such optimism, with further study of this therapy being strongly indicated. Michael J. Droller Department of Urology Mount Sinai Hospital New York, New York
REFERENCES 1. Morales, A., Eidinger, D. and Bruce, A. W.: Intracavitary bacillus Calmette-Guerin in the treatment of superficial bladder tumors. J. Urol., 116: 180, 1976. 2. Brosman, S. A.: The use of bacillus Calmette-Guerin in the therapy of bladder carcinoma in situ. J. Urol., 134: 36, 1985. 3. Morales, A.: Long-term results and complications of intracavitary bacillus Calmette-Guerin therapy for bladder cancer. J. Urol., 132: 457, 1984. 4. Lamm, D. L.: Bacillus Calmette-Guerin immunotherapy for bladder cancer. J. Urol., 134: 40, 1985. 5. Netto, N. R., Jr. and Lemos, G. C.: A comparison of treatment methods for the prophylaxis of recurrent superficial bladder tumors. J. Urol., 129: 33, 1983. 6. Kelley, D. R., Ratliff, T. L., Catalona, W. J., Shapiro, A., Lage, J. M., Bauer, W. C., Haaff, E. 0. and Dresner, S. M.: lntravesical bacillus Calmette-Guerin therapy for superficial bladder cancer: effect of bacillus Calmette-Guerin viability on treatment results. J. Urol., 134: 48, 1985. 7. Zbar, B., Ribi, E. and Rapp, H. J.: An experimental model for iinmunotherapy of cancer. Natl. Cancer Inst. Mongi'., 39: 3, 1973. 8. Lamm, D. L., Thor, D. E., Winters, W. D., Stogdill, V. D. and Radwin, H. M.: BCG imniunotherapy of bladder cancer: inhibition of tumor recurrence and associated immune responses. Cancer, 48: 82, 1981. 9. Lamm, D. L., Thor, D. E., Harris, S. C., Reyna, J. A., Stogdill, V. D. and Radwin, H. M.: Bacillus Calmette-Guerin immunotherapy of superficial bladder cancer. J. Urol., 124: 38, 1980. 10. Morales, A.: Treatment of carcinoma in situ of the bladder with BCG, a phase II trial. Cancer Immunol. Immunother., 9: 69, 1980. 11. Netto, N. R., Jr. and Lemos, G. C.: Bacillus Calmette-Guerin immunotherapy of infiltrating bladder cancer. J. Urol., 132: 675, 1984. 12. Lamm, D. L.: Personal communication. 13. Morales, A., Ottenhof, P. and Emerson, L.: Treatment of residual, non-infiltrating bladder cancer with bacillus Calmette-Guerin. J. Urol., 125: 649, 1981. 14. Adams, D. 0.: The granulomatous inflammatory response. A review. Amer. J. Path., 84: 164, 1976.
BACILLUS CALMETTE-GUERIN IN MANAGEMENT OF BLADDER Ct.NCER 15. Connolly, J. G.: Re: immunotherapy of superficial bladder cancer. Letter to the Editor. J. UroL, 130: 368, 1983. 16. Carswell, E. A, Old, L. J., Kassel, R. L., Green, S., Fiore, N. and
Williamson, R: An endotoxin-induced serum factor that causes necrosis of tumors. Proc. NatL Acad. Sci., 72: 3666, 1975. 17. Zacharchuk, C. M., Drysdale, B., Mayer, M. M. and Shin, H. S.: Macrophage-mediated cytotoxicity: role of a soluble macrophage cytotoxic factor similar to lymphotoxin and tumor necrosis factor. Proc. NatL Acad. Sci., 80: 6341, 1983. 18. Williamson, B. D., Carswell, E. A., Rubin, B. Y., Prendergast, J. S. and Old, L. J.: Human tumor necrosis factor produced by human B-cell lines: synergistic cytotoxic interaction with human interferon. Proc. NatL Acad. Sci., 80: 5397, 1983. 19. Sugarman, B. J., Aggarwal, B. B., Haas, P. E., Figari, I. S.,
333
Palladino, M. A., Jr. and Shepard, H. M.: Recombinant human tumor necrosis factor-a: effects on proliferation of normal and transformed cells in vitro. Science, 230: 943, 1985. 20. Farrow, G. M. and Utz, D. C.: Observations on microinvasive transitional cell carcinoma of the urinary bladder. Clin. Oncol., 1: 609, 1982. 21. Prout, G. R., Jr., Koontz, W. W., Jr., Coombs, L. J., Hawkins, I. R. and Friedel!, G. H. for National Bladder Cancer Collaborative Group A: Long-term fate of 90 patients with superficial bladder cancer randomly assigned to receive or not to receive thiotepa. J. Urol., 130: 677, 1983. 22. Droller, M. J. and Walsh, P. C.: Intensive intravesical chemotherapy in the treatment of flat carcinoma in situ: is it safe? J. Urol., 134: 1115, 1985.
THE JOURNAL OF UROLOGY
Copyright© 1986 by The Williams & Wilkins Co.
Printed in U.S.A.
Editorial BACILLUS CALMETTE-GUERIN IN THE MANAGEMENT OF BLADDER CANCER When the therapeutic effects of BCG were first reported Although bacillus Calmette-Guerin (BCG) long had been proposed for the treatment of cancer few expected as dramatic some suggested that the nonspecific inflammatory response an impact to be made as ultimately occurred when Morales and that resulted led to a generalized sloughing of cells, which associates first published their initial results on the use of BCG resulted in the elimination of neoplastic or preneoplastic cells in bladder cancer in 1976. 1 However, the articles in this issue as a bystander effect of the treatment. Early efforts to delineate of the Journal, as well as several others in recent issues, 2- 6 an immunological mechanism for the prophylactic effects that attest not only to the interest that was generated at that time were seen were unsuccessful,8 thereby indirectly confirming the but also to the astounding results that have been obtained. In nonspecific and possibly nonimmunological nature of BCG retrospect, perhaps this should not have been so surprising. treatment effectiveness. On the other hand, prophylactic and therapeutic success Results in experimental animal models had demonstrated that BCG would be effective against tumors if inoculated in close appeared to correlate with conversion of purified protein derivproximity to the tumor (direct contact), in appropriate dosage ative skin test responsiveness from negative to positive, 6 • 9 • 10 and in association with induction of an inflammatory (?immune implying that a systemic host reaction to intravesical instillaor hypersensitivity) response. 7 It was apparent from the original tion might either be a concomitant or a necessity for the work of Morales and associates that topical instillation of BCG therapeutic efficacy of BCG to be expressed. This concept was fulfilled all of these requirements. Moreover, numerous subse- supported further by observations that the number of viable quent reports documented the apparent efficacy of BCG instil- organisms actually inoculated into the bladder determined lation in the prevention of recurrent superficial bladder tumors whether prophylactic and therapeutic efficacy was achieved. 6 and effectively promoted this old therapeutic modality as a new Other reports describing prophylactic efficacy following oral and possibly more effective alternative to standard chemother- treatment with BCG5 and in some instances therapeutic effiapeutic prophylactic management of recurrent superficial blad- cacy for muscle-invasive bladder cancers on intravesical instillation of this agent11 • 12 further supported the hypothesis that der cancer. Not unexpectedly, therefore, was the excitement generated the induction of an immunological response (?hypersensitivity in the possible use of this agent in actual therapy as well. We reaction implicating T lymphocyte/macrophage stimulation are now beginning to see the initial results of studies reflecting and activation) might, indeed, be operative in the use of this this new and seemingly well founded interest. In a recent issue modality. Corresponding descriptions of a 77 per cent response of the Journal apparent successful therapy of residual tumor free of tumor in those bladders with a granulomatous reaction was documented in 54 per cent of the patients with a single compared with only a 32 per cent response in those lacking a BCG treatment and in an additional 2 of 5 initial failures granulomatous reaction6 confirmed earlier suggestions that this following a second course ofBCG. 6 In addition, complete regres- might be an important index of predicability of response, 1 • 13 as sion of carcinoma in situ was seen in 50 per cent of the patients, well as of the more deep-seated reaction necessary for satisfacand 3 of 5 with recurrent carcinoma in situ responded to a tory effectiveness to be achieved. Although some have observed second course ofBCG. 6 Similar treatment results for carcinoma that a granulomatous reaction to BCG can occur in the absence in situ were reported by Brosman, who suggested that two- of a delayed hypersensitivity response, 14 the cogency of evidence thirds of the patients responded to a 12-week course of therapy, remains in support of the concept that the systemic response while the 9 who did not respond initially were eventually to BCG instillation may be responsible, at least in part, for the rendered free of tumor following a 24-week course of therapy. 2 therapeutic response observed. Despite disclaimers by Kelley A similar therapeutic effect of BCG instillation (as contrasted and associates (page 268) that systemic responsiveness to BCG with a prophylactic effect) is confirmed by reports in this issue does not necessarily predict response to therapy, the correlation of the Journal. Schellhammer and associates (page 261) de- between apparent immune responsiveness to BCG and treatscribe a complete response in 71 per cent of the patients who ment results strongly suggests that systemic hypersensitivity had residual tumor after incomplete resection or with positive effects may hold a clue to the mechanism of action by BCG. selected site biopsies and/or post-resection positive cytology. Whether this mechanism is manifested by the simple sloughing Herr and associates (page 265) report that 68 per cent of 47 of the urothelium (and the bystander sloughing of neoplastic patients were free of carcinoma in situ (negative urine cytology, cells) as part of an inflammatory response possibly represented cystoscopy and biopsy) after a single 6-week course of intraves- by regional nonimmune granuloma formation, 15 or whether ical BCG therapy during a 4-year followup. These results appear there is an immune-inducing activity as represented by immune to extend the efficacy of BCG to a dramatic extreme if, in fact, granuloma formation with as yet poorly defined specificity for diffuse carcinoma in situ with its known progressive malignant tumor cells in the bladder remains to be determined. Perhaps basic to each of these possibilities is the role of potential can be eliminated successfully after such a short and various immunomodulatory proteins or cytokines that may be generally well tolerated course of relatively benign therapy. However, there clearly are many questions that remain un- produced in response to BCG. Most prominent among these is answered. Most prominent among these is the mechanism by the so-called tumor necrosis factor (TNF), a substance or which BCG exerts so profound a prophylactic/therapeutic ef- substances originally found to be produced in response to fect and the means by which this mechanism may interact with sequential treatment of mice with BCG and endotoxin. 16 TNFthe potential intrinsic behavior of a particular form of superfi- induced necrosis of implanted tumors in experimental animals with involvement of macrophages and lymphocytes, 17• 18 and cial (or in situ) bladder cancer. 331
332
DROLLER
possible synergism of cytotoxicity With interferon as produced under similar circumstances 19 may be analogous and especially applicable to the clinical situation presented by bladder cancer and its apparent response to BCG. These possibilities merit further investigation. The interaction of the response to BCG with the intrinsic biological behavior of a particular neoplasm is equally as intriguing because of the mystery it presents. This appears to be especially striking in the case of carcinoma in situ. Whereas 75 per cent of the patients with diffuse carcinoma in situ (20 to 30 per cent of whom already have microscopic penetration of tumor into the lamina propria) have traditionally been expected to have progressive bladder cancer and require cystectomy, 20 it would appear from the present reports of Schellhammer and Herr and their associates as well as earlier studies2• 6 that many of these patients can be rid of the disease after a single course of BCG, and that the majority can be cured upon extension of this course. If urothelial sloughing as the result of direct contact with an inflammatory reaction to BCG is responsible for its therapeutic efficacy, this may not be an entirely surprising result with in situ involvement of the bladder. However, it is a surprising result for those patients in whom the prostatic urothelium has been involved by in situ disease. This is especially true in those patients who have not undergone resection of the prostate and in whom direct contact of BCG with the site of tumor might be questioned. In those instances therapeutic response may reflect a systemic effect of BCG but it also may reflect the possibility of reflux of ECG-containing urine into the prostatic ducts during micturition. Findings of granlilomatous prostatitis reported by Lamm and associates (page 272) in a number of patients undergoing BCG instillation are compatibie with both possibilities, although in each case one might have expected to find this as a more common occutrence, given the apparent number of therapeutic responses that have been reported. Notwithstanding these encouraging findings, there are several important caveats that must be considered.. The first is that an interpretation of many of the apparently successful results presently being reported may actually be dependent upon whether the diagnosis of the carcinoma in situ lesion is real. Since accurate diagnosis of this lesion often is based entirely on interpretation of urinary cytology and interpretation of urinary cytology currently is an area of major controversy with varying agreement among expert pathologists, it is questionable whether the diagnosis of this lesion can truly be made with the consistency and uniformity that are necessary to assess these results. Furthermore, might it not be possible that pathologists have been more likely in recent years to diagnose cancer cells when they assumed that this wouid result in a course of BCG instillation? This would be consistent with what was seen in previous years when pathologists were reluctant to make a diagnosis of carcinoma in situ when they thought that this would lead to cystectomy. That infiltration of cancer in prostatic ducts may make such cancer inaccessible to topical BCG therapy also is a critical consideration. Since microscopic stromal infiitration often may be seen in these areas when additional sections are examined, such patients may be at serious risk of cancer progression despite apparent superficial control as diagnosed endoscopically or cytologically. it also may turn out that different forms of superficial cancer or carcinoma in situ may have varying susceptibility to BCG treatment. Presently, such variability is unpredictable. Indeed, progressive disease has been documented in our patients as well as those of Kelley and associates6 treated with BCG in whom significant prostatic involvement was found and persisted despite intensive therapy, and in others reported on by Herr and associates in whom muscle-infiltrating tumor also was found at variable intervals after initiation of BCG treatment for "superficial" tumor or carcinoma in situ. These obser-
vations, not unlike previous results with other forms of intravesical therapy for superficial bladder tumors or carcinoma in situ, 21 • 22 highlight the unpredicability of many of the lesions being treated and underscore the need to identify more clearly prognostic factors that may permit suitable intensive therapy for those patients likely to respond and more radical surgical therapy for those who remain at serious risk from the disease. Taken together, we may be at the forefront of a major change in our ability to manage bladder cancer. Certainly, BCG therapy as reported by Lamm and associates in multiple centers is safe in most patients. If, indeed, BCG has a systemic effect and if there is something unique about the transitional epithelium that allows an immune or an inflammatory response to BCG stimulation to eradicate successfully not only superficial disease in the bladder but also infiltrative disease in the bladder and in the prostatic urethra as well, then might it ultimately not be conceivable to apply such therapy even to those patients with more advanced regional bladder cancer in combination with one of the current systemic chemotherapy protocols to eradicate clinically apparent and/or subclinical metastatic disease? The painting of such an optimistic picture obviously is premature and must be shaded by consideration of the aforementioned caveats. Nonetheless, the results reported in this issue of the Journal and in previous issues may well represent a valid stimulus for such optimism, with further study of this therapy being strongly indicated. Michael J. Droller Department of Urology Mount Sinai Hospital New York, New York
REFERENCES 1. Morales, A., Eidinger, D. and Bruce, A. W.: Intracavitary bacillus Calmette-Guerin in the treatment of superficial bladder tumors. J. Urol., 116: 180, 1976. 2. Brosman, S. A.: The use of bacillus Calmette-Guerin in the therapy of bladder carcinoma in situ. J. Urol., 134: 36, 1985. 3. Morales, A.: Long-term results and complications of intracavitary bacillus Calmette-Guerin therapy for bladder cancer. J. Urol., 132: 457, 1984. 4. Lamm, D. L.: Bacillus Calmette-Guerin immunotherapy for bladder cancer. J. Urol., 134: 40, 1985. 5. Netto, N. R., Jr. and Lemos, G. C.: A comparison of treatment methods for the prophylaxis of recurrent superficial bladder tumors. J. Urol., 129: 33, 1983. 6. Kelley, D. R., Ratliff, T. L., Catalona, W. J., Shapiro, A., Lage, J. M., Bauer, W. C., Haaff, E. 0. and Dresner, S. M.: lntravesical bacillus Calmette-Guerin therapy for superficial bladder cancer: effect of bacillus Calmette-Guerin viability on treatment results. J. Urol., 134: 48, 1985. 7. Zbar, B., Ribi, E. and Rapp, H. J.: An experimental model for iinmunotherapy of cancer. Natl. Cancer Inst. Mongi'., 39: 3, 1973. 8. Lamm, D. L., Thor, D. E., Winters, W. D., Stogdill, V. D. and Radwin, H. M.: BCG imniunotherapy of bladder cancer: inhibition of tumor recurrence and associated immune responses. Cancer, 48: 82, 1981. 9. Lamm, D. L., Thor, D. E., Harris, S. C., Reyna, J. A., Stogdill, V. D. and Radwin, H. M.: Bacillus Calmette-Guerin immunotherapy of superficial bladder cancer. J. Urol., 124: 38, 1980. 10. Morales, A.: Treatment of carcinoma in situ of the bladder with BCG, a phase II trial. Cancer Immunol. Immunother., 9: 69, 1980. 11. Netto, N. R., Jr. and Lemos, G. C.: Bacillus Calmette-Guerin immunotherapy of infiltrating bladder cancer. J. Urol., 132: 675, 1984. 12. Lamm, D. L.: Personal communication. 13. Morales, A., Ottenhof, P. and Emerson, L.: Treatment of residual, non-infiltrating bladder cancer with bacillus Calmette-Guerin. J. Urol., 125: 649, 1981. 14. Adams, D. 0.: The granulomatous inflammatory response. A review. Amer. J. Path., 84: 164, 1976.
BACILLUS CALMETTE-GUERIN IN MANAGEMENT OF BLADDER Ct.NCER 15. Connolly, J. G.: Re: immunotherapy of superficial bladder cancer. Letter to the Editor. J. UroL, 130: 368, 1983. 16. Carswell, E. A, Old, L. J., Kassel, R. L., Green, S., Fiore, N. and
Williamson, R: An endotoxin-induced serum factor that causes necrosis of tumors. Proc. NatL Acad. Sci., 72: 3666, 1975. 17. Zacharchuk, C. M., Drysdale, B., Mayer, M. M. and Shin, H. S.: Macrophage-mediated cytotoxicity: role of a soluble macrophage cytotoxic factor similar to lymphotoxin and tumor necrosis factor. Proc. NatL Acad. Sci., 80: 6341, 1983. 18. Williamson, B. D., Carswell, E. A., Rubin, B. Y., Prendergast, J. S. and Old, L. J.: Human tumor necrosis factor produced by human B-cell lines: synergistic cytotoxic interaction with human interferon. Proc. NatL Acad. Sci., 80: 5397, 1983. 19. Sugarman, B. J., Aggarwal, B. B., Haas, P. E., Figari, I. S.,
333
Palladino, M. A., Jr. and Shepard, H. M.: Recombinant human tumor necrosis factor-a: effects on proliferation of normal and transformed cells in vitro. Science, 230: 943, 1985. 20. Farrow, G. M. and Utz, D. C.: Observations on microinvasive transitional cell carcinoma of the urinary bladder. Clin. Oncol., 1: 609, 1982. 21. Prout, G. R., Jr., Koontz, W. W., Jr., Coombs, L. J., Hawkins, I. R. and Friedel!, G. H. for National Bladder Cancer Collaborative Group A: Long-term fate of 90 patients with superficial bladder cancer randomly assigned to receive or not to receive thiotepa. J. Urol., 130: 677, 1983. 22. Droller, M. J. and Walsh, P. C.: Intensive intravesical chemotherapy in the treatment of flat carcinoma in situ: is it safe? J. Urol., 134: 1115, 1985.