Bladder Cancer Immunotherapy

0022-534 7/82/1285-0931$02.00/0 Vol. 128, November

THE JOURNAL OF UROLOGY

Printed in U.S.A.

Copyright© 1982 by The Williams & Wilkins Co.

BLADDER CANCER IMMUNOTHERAPY DONALD L. LAMM, DANIEL E. THOR, VALERIE D. STOGDILL

AND

HOWARD M. RADWIN

From the Department of Surgery, Division of Urology, and Departments of Microbiology and Pathology, University of Texas Health Science Center and Audie Murphy Veterans Administration Hospital, San Antonio, Texas

ABSTRACT

A randomized controlled prospective evaluation of intravesical and percutaneous bacillus Calmette-Guerin immunotherapy was done on 57 patients with transitional cell carcinoma of the bladder. In addition, 9 patients at high risk for tumor recurrence were treated with bacillus CalmetteGuerin. Intravesical bacillus Calmette-Guerin produced a self-limited cystitis and 1 complication (hydronephrosis) of immunotherapy was observed. Of the 57 randomized patients 54 were followed for 3 to 30 months. Tumor recurrence was documented in 13 of 26 controls (50 per cent) and only 6 of 28 patients (21 per cent) treated with bacillus Calmette-Guerin (p equals 0.027, chi-square). The interval free of disease was prolonged significantly with bacillus Calmette-Guerin treatment (p equals 0.014, generalized Wilcoxon test). Importantly, a simple purified protein derivative skin test distinguished those patients who responded to bacillus Calmette-Guerin immunotherapy from those who did not. Only 1 of 17 treated patients (6 per cent) whose purified protein derivative test converted from negative to positive had tumor recurrence compared to 5 recurrences (38 per cent) among the 13 patients whose test remained negative or had been positive before treatment (p equals 0.022, chi-square). Bacillus Calmette-Guerin was given to 10 patients with stage B transitional cell carcinoma who were not candidates for cystectomy and 7 are free of disease. Of 5 patients with carcinoma in situ 3 remain free of tumor after bacillus Calmette-Guerin treatment and 5 of 6 who had multiple recurrences after intravesical chemotherapy responded favorably to bacillus CalmetteGuerin immunotherapy. Approximately 75 per cent of the 35,000 patients who suffer bladder cancer annually subsequently will have recurrent tumors. Such recurrences increase frequently in stage and grade. Even with the use of intravesical chemotherapy, such as thiotepa, 23 to 58 per cent of the patients still suffer tumor recurrence. 1 In May 1979 we presented the preliminary results of our controlled evaluation of bacillus Calmette-Guerin (BCG) immunotherapy in patients with superficial bladder cancer. 2 In that study bladder tumor recurrences were reduced to 17 per cent of the patients. Since then we have continued to observe a most favorable response to BCG immunotherapy. The benefits of BCG in the treatment of patients with bladder cancer have been confirmed independently in a controlled study. 3 We herein report our experience with BCG in the treatment of patients with superficial and invasive transitional cell carcinoma of the bladder and carcinoma in situ, and those who have failed to respond to intravesical chemotherapy. MATERIALS AND METHODS

Since January 1978, 57 patients with confirmed transitional cell carcinoma of the bladder have enrolled in a prospective protocol. Patients were stratified according to tumor grade (I versus ~II) and number of previous recurrences (0 to 1 versus ~2 in the most recent year). All patients had primary or recurrent tumor within 3 years of enrollment. Patients were assigned by closed envelope to receive either standard surgical therapy (29 controls) or standard surgical therapy plus BCG immunotherapy (30 patients). Stratification resulted in control and treatment groups with a similar mean tumor grade (2.0) and number of previous recurrences (mean 1.3, range O to 6 for controls and mean 1.2, range Oto 6 for the BCG group). The mean patient age for both groups was 66 years. Five patients had a history of stage B bladder cancer but were not candidates for cystectomy. Of these 5 patients 4 were randomized to the Accepted for publication December 18, 1981. Read at annual meeting of American Urological Association, Boston, Massachusetts, May 10-14, 1981. 931

treatment group, resulting in an increased mean tumor stage for the BCG group. The mixed cell adherence assay for the presence of A, B or H antigens on resected tumors was performed on 22 treatment and 21 control patients as described previously. 4 Immunotherapy. BCG immunotherapy was performed as described by Morales and associates. 5 Lyophylized Pasteur strain BCG was administered intravesically and percutaneously at weekly intervals for 6 weeks, beginning 1 to 2 weeks after transurethral resection of the bladder tumor and/or at entry into the protocol. A suspension containing 120 mg. BCG in 50 cc normal saline was given intravesically and 5 mg. were given percutaneously into alternate upper thighs using a Heaf gun. Evaluation. Both patient groups were followed at regular 3 to 6-month intervals with cystoscopic examinations, and all recurrent tumors were resected transurethrally and examined microscopically. Additional treatment, including cystectomy, intravesical chemotherapy or radiation therapy, was administered as indicated clinically to patients in each group. Patients were monitored for complications of BCG therapy with complete blood count, blood urea nitrogen, creatinine, alkaline phosphatase, and serum glutamic oxaloacetic transaminase determinations after the 3 treatments and at 3, 6 and 12 months. Treatment and control patients were skin tested intradermally with purified protein derivative (PPD), Candida and Trichophyton antigens on admission to the protocol, and at 3 to 6-month intervals thereafter. Cellular immunity to PPD antigens was evaluated by leukocyte migration inhibition assay as described previously. 6 RESULTS

Side effects of BCG immunotherapy were minor in patients with superficial disease and only 1 complication occurred. Irritative vesical symptoms were common and increased generally with subsequent treatments. Of the patients 96 per cent had dysuria and 86 per cent had frequency. Symptoms resolved generally after 2 days of treatment. Surprisingly, in some pa-

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tients with pre-existing dysuria secondary to carcinoma in situ prompt improvement in symptoms occurred with BCG treatment. Mild hematuria was seen in 34 per cent of the patients and fever was noted in 21 per cent. Fever was 102F. Of these 2 patients 1 had fever to 105F with shaking chills. Repeated BCG immunotherapy in this patient at 3 and 6 months again was associated with fever as high as 103F despite the concurrent administration of isoniazid. At 9 months administration of 60 mg. BCG intrav€sically resulted in fever, malaise and severe cystitis, producing bilateral partial ureteral obstruction that increased serum creatinine to 5.0 mg. per cent. Hydronephrosis improved during the next week and serum creatinine returned to 1.1. Nausea was seen in 14 per cent of the patients, and chills and malaise were noted in 3 per cent each. No weight loss, disseminated BCG infection, allergic reaction, cytopenia or decreased bladder capacity related to BCG immunotherapy was found. Followup ranged from 3 to 30 months in 26 controls and 28 patients treated with ECG. The remaining 6 patients were

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followed for <3 months. Of the 26 controls 13 (50 per cent) suffered recurrent tumors compared to 6 of the 28 patients treated with BCG (21 per cent, p = 0.027, chi-square). The mean time to recurrence in the control group was 16 months compared to 29 months in the treatment group. A comparison of Kaplan-Meier curves for time to recurrence revealed the delay in tumor recurrence to be significant at a p = 0.014 level (fig. 1). A total of 28 episodes of tumor recurrence (89 individual tumors) was noted in the control group compared to 12 episodes (27 tumors) in the BCG group (fig. 2). The decrease in tumor recurrence after BCG immunotherapy was most prominent at the initial 3-month followup cystoscopic examination. Of the control patients 27 per cent had tumor recurrence within 3 months compared to 4 per cent of the patients treated with BCG (p = 0.024, Fisher's exact test). It is unlikely that the marked decrease in tumor recurrence in the BCG group at 3 months is the result of the inability to visualize tumor in the presence of BCG cystitis, since only 1 patient had tumor recurrence at subsequent examination when inflammation resolved. When the total episodes of recurrence are compared 28 of 117 cystoscopic examinations in the control group were positive for tumor compared to 12 of 118 examinations in the BCG group (p = 0.005, chi-square). Surprisingly, when patients were separated according to the presence or absence of ABH antigens on the tumor the more aggressive ABH-negative tumors were found to recur less frequently than ABH-positive tumors. Kaplan-Meier curves for time to recurrence for all patients in the randomized study for whom ABH antigenicity could be determined revealed a prolongation in time to recurrence in ABH-negative patients, irrespective of treatment status, which was significant at the p = 0.05 level (Savage test) (fig. 3). Only 1 of the 6 patients treated with BCG with recurrent tumor had an ABH-negative test. Prior tumor grade had no significant effect on tumor recurrence. In the BCG group 1 of 4 patients with grade I, 4 of 22 with grade II and 1 of 4 with grade III tumors had recurrence, while in the control group 1 of 2 patients with grade I, 11 of 21 with grade II and l of 3 with grade III tumors had recurrence. The 6 patients who suffered recurrent bladder tumor despite BCG immunotherapy had evidence of impaired immune response to BCG. Of these 6 patients 3 were among the 13 patients treated with BCG who failed to have cellular immunity to PPD. More importantly, correlation with the simple PPD skin test was apparent and statistically significant. The PPD skin test was considered positive if ~10 mm. induration occurred in response to intermediate strength PPD. Only l of 17 patients

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stage B transitions.I cell carcinorna in additio:n to c2;.:rcinorr1a in situ. After BCG rrc,m,Uil01tl1J3l'.2 random ,-.,J~m,oLl revealed no carcinoma in situ but radiation was required for residual invasive disease, The last patient also had deeply invasive disease with residual tumor documented 3 months after imand ----~--·· underwent radical cystectomy,

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FIG, 3, Kaplan-Meier curves for time to recurrence for all ABHnegative and ABH-positive tumors, regardless of treatment group show surprising decrease in tumo:r recurrence in ABE-negative tumors,

treated with BCG (6 per cent) whose PPD test converted from negative to positive had tumor recurrence compared to 5 recurrences (38 per an1ong 13 patients whose test remained negative or was positive before imrnunotherapy (p = 0,022), Of the 6 patients who had skin tests before BCG 3 (50 per cent) suffered recurrent tumor ,,,,m,,Q>'<>n to 2 of 7 (29 per whose skin test remained after BCG, The 1 had tumor recurrence later had a skin test on subseSeven similar patients vvho had a '""~"'"r, PPD test after BCG immunotherapy later had a n~,,,,,uv,e test, ranging from 6 to 18 months after BCG irnmunotherapy (mean 12 months). As expected, skin test reactivity to Candida and Trichophyton antigens did not correlate with tumor recurrence. In the control group only 5 per cent of the no,,,u,nira had an increase in Candida and/or 1cJ1opbtvt;on skin test reactions on subsequent while 40 per cent with BCG had an skin test

BCG cancer, vvho either refused candidates, were treated with 4 were included in the randomized 6 of these patients have remained free of tumor for a mean 14 months (range 3 to 36 months). 2 suffered mul, p21we11c, who has been described rnonths after BCG tiatio:r1 c,f In&intenance had residual tumor 3 nwnths after initiation of tres,tment: 2 and 1 under-v,.rere treated 1.vit~1 radiaticn vvent cystectomy. had tun-.aor TecurYences In our series 6 treatment with

free of tumor, with a mean had recurrence 17 months after and ~,,,,,_,, ~,eh, is free of tumor after a course of rnunotherapy, The remaining patient was an 85-year-old man who failed to respond to BCG immunotherapy, suffered tumor recurrence at 3 months and subsequently was treated with radiation Of 5 patients with carcinoma in situ treated with BCG 3 remain free of tumor as documented by negative cytology studies and random biopsy at a mean of 15 months after therapy, One patient, an 82-year-old man with congestive heart failuTe and diabetes mellitus, had an incompletely resected

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Case 6, A 75-year-old man, included in our initial report,2 presented with hematu:ria and positive urinary cytology studies, There was a flat tumor overlying the trigone, and right and left posterior bladder, Cystoscopically, it was estimated that 70 per cent of the bladder was involved with tumor, Wide resection and fulguration were done but it was considered unlikely that complete tumor resection could be accomplished, Histologically, extensive grades II to III transitional cell carcinoma with muscle invasion was found, The patient refused cystectorny and was assigned randomly to receive BCG immunotherapy, Random bladder biopsies 3 weeks after BCG treatment revealed chronic inflammation and granulomas but no tumor, Subsequent evaluation with repeated urinary cytology studies, cystoscopy and random bladder biopsies have demonstrated no tumor and the patient has remained free of tumor for >40 months after BCG therapy, Case 69, A 64-year-old man presented with a history of 3 transurethral resections for grades II to III, stage A transitional cell carcinoma of the bladder. Tumors recrnred despite weekly intravesical thiotepa chemotherapy therefore, the patient was referred for immunotherapy, At hospitalization a grade III to IV, stage B transitional cell carcinoma on the right posterior bladder was resected and random demonstrated diffuse caxcinoma in situ, The patient was a poor candidate for cystectomy owing to Crohn's disease, which :required previous colectomy and multiple small bowel resections with subsequent enterovesical and enterocutaneous fistulas, and abscesses, Therefore, BCG rrnmunotherapy was administered and treatments were complicated by feveTs as high as 105F, malaise and ureteral obstruction as described previously, Cystoscopy and multiple biopsies 3 months later demonstrated chronic inflammation and granulomatous reaction, One microscopic section showed of abnormal cells consistent with transitional cell carcinoma, The patient was treated with an additional intravesical and percutaneous administration of BCG and rebiopsy and cytology studies 3 months latex vu,,-,,,u,v resolution of carcinoma in situ, He remained free of tumor, vvith negative random biopsies for 9 months after the initiation of L'Timunotherapy. Case 71, A man ""'"Hetu with hematuria and HI to IV solid -undeI'"'Nent which transitional cell obliterated the bimanual urete:rnJ orifice, tumor was examination the lesion to be at least studies confirmed muscle invasion, ,,,,,ot, 1,,wnu and radiation therefore. was intravesical and percutaneous BCG, Compute~·ized scan, cystoscopy, and cytology studmonths shm11ed complete regression tumox and the has remained free of disease, as confirmed repeated cystoscopy and transurethral biopsy, for 1 year, 0 "

DISCUSSION

Our experience with 39 patients treated with BCG immunotherapy confirms the relative safety of intravesical and percutaneous immunotherapy, Intravesical administration permits juxtaposition of BCG organisms and tumor, Therefore, the advantages of local BCG immunotherapy are provided, while potentially avoiding the increased incidence of serious complications, such as hepatic dysfunction, disseminated BCG infection, anaphylaxis and sepsis, which have been associated with

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LAMM AND ASSOCIATES

intralesional BCG therapy. 7 The cystitis produced by BCG, which is symptomatic for l to 3 days in most patients, may be an essential component of the antitumor effect. Stimulated by BCG lymphocytes and macrophages can kill or inhibit the growth of tumor cells by direct contact or by the release of tumoricidal factors. 8 Although several of the patients in the randomized study had fever
candidates. Further study is indicated to explore the potential of BCG immunotherapy in these difficult patients. Since immunotherapy typically is not effective in the face of a large tumor burden it seems likely that few patients would have a complete response within the bladder if extravesical extension or nodal metastases were present. If this favorable response in nonsurgical candidates is representative of all patients with stage B disease, BCG immunotherapy may offer significant therapeutic advantages to a number of patients and may provide a means of selecting those who are candidates for more aggressive treatment. Presently, immunotherapy appears to offer a potentially excellent alternative therapy for these difficult patients. The experience in patients who had recurrences of bladder tumor despite intravesical thiotepa chemotherapy is encouraging, since 23 to 58 per cent of the patients who are treated with thiotepa subsequently will have tumors. Four of 6 patients who failed to respond to thiotepa remain free of tumor after BCG immunotherapy. Thiotepa administration in these patients was discontinued before BCG administration since local chemotherapy or radiation therapy would be expected to inhibit the proliferation of plasma cells, macrophages and lymphocytes that infiltrate the bladder in response to BCG. In theory, carcinoma in situ should be an ideal lesion for treatment with nonspecific immunotherapy. Carcinoma in situ provides a lesion that has a small tumor volume and, yet, permits broad, direct contact of BCG and tumor antigens. Our limited experience with 5 patients, 3 of whom had complete resolution of carcinoma in situ after BCG, is comparable to the experience of others. 10' 11 The only failures in our experience occurred in patients who had unresectable, residual invasive carcinoma in addition to carcinoma in situ. Despite the failure of BCG to produce consistently prolongation of survival in other human tumors, the remarkable and statistically significant decrease in tumor recurrence and the observed instances of resolution of carcinoma in situ, as well as incompletely resected invasive carcinoma, lead one to expect that such therapy will improve the morbidity and mortality of bladder cancer. Although the relative merits of BCG immunotherapy compared to intravesical chemotherapy remain undetermined, the dramatic results obtained with BCG suggest that further trials comparing BCG immunotherapy with optimal intravesical chemotherapy should be performed. REFERENCES 1.

2. 3. 4. 5. 6. 7. 8. 9.

10.

Soloway, M. S.: Rationale for intensive chemotherapy for superficial bladder cancer. J. Urol., 123: 461, 1980. Lamm, D. L., Thor, D. E., Harris, S. C., Reyna, J. A., Stogdill, V. D. andRadwin, H. M.: Bacillus Calmette-Guerinimmunotherapy of superficial bladder cancer. J. Urol., 124: 38, 1980. Camacho, F., Pinsky, C., Kerr, D., Whitmore, W. and Oettgen, H.: Treatment of superficial bladder cancer with intravesical BCG. Proc. Amer. Soc. Clin. Oncol., 21: 359, 1980. Johnson, J. D. and Lamm, D. L.: Prediction of bladder tumor invasion with the mixed cell agglutination test. J. Urol., 123: 25, 1980. Morales, A., Eidinger, D. and Bruce, A. W.: Intracavitary bacillus Calmette-Guerin in the treatment of superficial bladder tumors. J. Urol., 116: 180, 1976. Lavergne, J. A., Lamm, D. L., Radwin, H. M. and Harrington, J. T.: Leukocyte migration inhibition in vitro in bladder carcinoma. Cancer Res., 39: 1985, 1979. Robinson, J. C.: Risks of BCG intralesional therapy: an experience with melanoma. J. Surg. Oncol., 9: 587, 1977. Bast, R. C. and Bast, B. S.: Critical review of previously reported animal studies of tumor immunotherapy with nonspecific immunostimulants. Ann. N. Y. Acad. Sci., 277: 60, 1976. Lamm, D. L., Thor, D. E., Winters, W. D., Stogdill, V. D. and Radwin, H. M.: BCG immunotherapy of bladder cancer: inhibition of tumor recurrence and associated immune responses. Cancer, 48: 82, 1981. Morales, A.: Treatment of carcinoma in situ of the bladder with

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BCG, a phase II trial. Cancer Immunol. lmmunother., 9: 69, 1980. 11. Herr, H. W., Pinsky, C. M., Whitmore, W. F., Jr., Oettgen, H., Kerr, D. and Camacho, F.: Effects of intravesical bacillus CalmetteGuerin (BCG) on carcinoma in situ of the bladder. Abstract 588. Read at annual meeting of the American Urological Association, Boston, Massachusetts, May 10-14, 1981. EDITORIAL COMMENT These authors document an apparent prophylactic effect of BCG in the treatment of superficial transitional cell carcinoma of the bladder, and an apparent therapeutic effect on carcinoma in situ and on stage B transitional cell cancer in selected patients. An inflammatory response is well documented in this as well as previous reports on such treatment. Enhancement of an immune response and the role of an immune response in the prevention of tumor recurrence and in tumor treatment are not well documented. Indeed, the effects seen may represent the byproduct of a nonspecific inflammatory response rather than a specifically directed immune response against that particular cancer. Moreover, it remains to be seen whether those patients with stage B tumor do experience successful therapy of the disease, since the possibility that BCG will produce systemic immunity with subse-

quent control of any subclinical metastatic disease does not have good precedent from patients treated previously for disseminated malignancy with BCG. Nonetheless, these authors are to be congratulated for their careful study of this intriguing means of treating superficial transitional cell cancer, a means that clearly needs additional clinical and experimental study. Michael J. Droller Brady Urological Institute The Johns Hopkins Hospital Baltimore, Maryland

REPLY BY AUTHORS Urologists and their patients will agree that the best possible documentation of immune response to BCG is the prevention of tumor recurrence. Such protection is the important bottom line, regardless of whether it is the result of inflammation or enhancement of specific immunity. We agree that BCG immunotherapy, like radiation therapy or an operation, is not expected to control metastatic disease, and we do not advocate its use in such patients.