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Oral bropirimine immunotherapy of carcinoma in situ of the bladder: results of a phase II trial
RAPID COMMUNICATION
ELSEVIER
ORAL BROPIRIMINE IMMUNOTHERAPY OF CARCINOMA IN SITU OF THE BLADDER: RESULTS OF A PHASE II TRIAL MICHAEL F. SAROSDY, BRUCE A. LOWE, PAUL F. SCHELLHAMMER, DONALD L. LAMM, SAM D. GRAHAM, JR., H. BARTON GROSSMAN, WILLIAM A. SEE, JAMES O. PEABODY, TIMOTHY D. MOON, ROBERT C. FLANIGAN, E. DAVID CRAWFORD, AND JOEL MORGANROTH
ABSTRACT Objectives. Bropirimine is an orally administered immunostimulant that has been shown to have activity against carcinoma in situ (CIS) of the bladder. To further assess this potential activity, bropirimine was administered to 42 patients for bladder CIS in a Phase II trial. Methods. Patients were treated with bropirimine 3.0 g/day by mouth for 3 consecutive days each week up to I year. Cystoscopy with biopsies and bladder wash cytology were performed quarterly. Results. Twenty (61%) of 33 evaluable patients converted malignant biopsies and bladder wash cytology to negative, including 6 (50%) of 12 who failed prior bacillus Calmette-Gu6rin (BCG) immunotherapy, 14 (67%) of 21 who had not received prior BCG therapy, and 12 (80%) of 15 with primary CIS. Median response duration exceeds 21 months. Four of the 20 responders did have a papillary tumor recurrence at 3 to I S months, all Stage Ta or TI. Mild toxicity (grade I or II) suggestive of interferon induction or administration occurred in one third of patients. Headache, transient hepatic enzyme elevations, skin rash, and arthralgias each occurred in 5% to 14% of the patients, with nausea or emesis in 21%. Grade i tachycardialpalpitations or chest pain each were noted in 5%. Conclusions. Oral bropirimine can induce remission of bladder CIS with acceptable toxicity at 3.0 g/day. Bropirimine may be a valuable alternative to cystectomy for some failures of BCG therapy and may have the potential to replace BCG as frontline therapy because of its ease of administration. UROLOGY 48: 21-27, 1996.
arcinoma in situ (CIS) of the bladder is a high-grade intraepithelial cancer that occurs C as an isolated lesion or coexists with papillary tumors in 10% to 20% of cases of bladder can-
From the Departments of Urology: University of Texas Health Science Center, San Antonio, Texas; Oregon Health Science University, Portland, Oregon; Eastern Virginia Medical School, Norfolk, Virginia; West Virginia University, Morgantown, West Virginia; Emory Clinic, Atlanta, Georgia; University of Michigan, Ann Arbor, Michigan; University of Iowa Hospital and Clinic, Iowa City, Iowa; Henry Ford Hospital, Detroit, Michigan; University of Wisconsin Hospital and Clinic, Madison, Wisconsin; Loyola University Medical Center, Maywood, Illinois; and University of Colorado Health Sciences Center, Denver, Colorado; and the Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania Present address of H. Barton Grossman is University of Texas, M.D, Anderson Cancer Center, Houston, Texas Reprint requests: Michael F. Sarosdy, M.D., Division of Urology, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78284-7845 Submitted: January 9, 1996, accepted (with revisions): March 11, 1996 COPYRIGHT 1996 BY ELSEVIER SCIENCE INC. ALL RIGHTS RESERVED
cer. 1-7 Intravesical i m m u n o t h e r a p y with bacillus Calmette-Gu~rin (BCG) has efficacy against superficial bladder cancer and is also the drug of choice for the treatment of CIS; it was approved by the Food and Drug Administration (FDA) in 1990. 8.9 However, controversy remains regarding the optimal duration and n u m b e r of treatments. It is clear that not all patients respond to BCG and that some who do respond will eventually relapse. ~°-14 Toxicity of intravesical BCG can be substantial, and treatment-related fatalities have occurred.15'~6 Alternative treatments for bladder CIS are needed. Bropirimine ( 2 - a m i n o - 5 - b r o m o - 6 - p h e n y l - 4 (3H)-pyrimidinone; Pharmacia & Upjohn, Inc., Kalamazoo, Mich) is an orally active immunomodulator that increases endogenous alpha-interferon and other cytokines; it also activates several cell-mediated immunologic defense mechanisms. 17-2° Based upon in vivo laboratory studies, 21,= a pilot trial of bropirimine was performed in patients with superficial bladder cancer. That 0090-4295/96/$15.00 PII S 0 0 9 0 - 4 2 9 5 ( 9 6 ) 0 0 0 5 9 - 3
21
TABLE I.
Patient characteristics
Age (years) Sex Male Female Southwest Oncology Group performance status (all patients) 0 1 2 Type of carcinoma in situ Primary Secondary Unifocal Multi focal *
37-81 (median 68) 38
4
35 5 2 15 18 8 25
Evaluable patients only.
TABLE
Completeresponse by prognostic factors
II.
Age ->70 years Age <70 years Primary CIS Secondary CIS Unifocal CIS Multifocal CIS Prior therapy None Prior chemotherapy only Prior BCG only Prior chemotherapy and BCG
11117 (65%) 9/16 (56%) 12115 (80%) 8/18 (44%) 6/8 (75%) 14/25 (56%} 8/12 6/9 2/7 4/5
(67%) (67%) (29%) (80%)
KEy: CIS = carcinoma in situ; BCG = bacillus Calmette-Ga~rin.
study indicated activity of bropirimine, chiefly in CIS. z3 E f f i c a c y w a s n o t e d b o t h i n p a t i e n t s w h o h a d previously been treated with BCG or intravesical i n t e r f e r o n , as w e l l as i n p a t i e n t s n o t p r e v i o u s l y treated. To confirm and further assess this activity, a m u l t i c e n t e r P h a s e II t r i a l o f o r a l b r o p i r i m i n e i n p a t i e n t s w i t h CIS o f t h e b l a d d e r w a s u n d e r t a k e n . MATERIAL
AND METHODS
The trial was a multicenter phase II study. Patients were required to have pathologically proven CIS without muscleinvasive disease, as well as six-site bladder and prostatic urethral biopsy mapping within 4 weeks of registration. Patients with concomitant papillary tumor (s) were eligible only if the papillary tumor (s) had been resected. A cytologicallypositive bladder wash obtained at least 24 hours after biopsy was required to confirm the continued presence of CIS. Patients with a prostatic urethral biopsy positive for CIS were eligible, and all patients were eligible regardless of prior therapy unless that included bropirimine. Patients were categorized as having CIS alone or in conjunction with resected papillary Stage Ta or T 1 tumors. Other descriptors included extent of bladder involvement (unifocal/multifocal), prior intravesical therapy 2:2
(none, BCG, or chemotherapy), and primary versus secondary C1S. Patients were required to have a Southwest Oncology Group performance status of 0 to 2, and normal liver, renal, and hematologic functions. All patients gave written informed consent. Bropirimine was formulated in compressed tablets containing 250 mg micronized nonhygroscopic drug. Dosing was initiated at least 1 week after bladder biopsies and after gross hematuria had cleared. Patients received oral bropirimine 3.0 g/day each evening for three consecutive nights weekly for 12 weeks. The total daily dose was divided into three equal fractions ( 1.0 g each) administered at 2-hour intervals (based upon previous pharmacokinetic studies) and self-administered on an outpatient basis. Compliance was assessed by comparison of dispensed and returned pill counts for each patient. Patients tolerating therapy were treated for 12 consecutive weeks followed by cystoscopy, bladder biopsies, and bladder wash cytology. Patients with progressive disease (Stage T2 or greater) were removed from the study. Patients with stable disease (no change) at I2 weeks were allowed to continue therapy for an additional 12 weeks, with subsequent identical re-evaluation. Patients who had a complete response at either 12 or 24 weeks were allowed to complete 1 year of therapy, at which time bropirimine was discontinued. Complete response was defined as conversion of biopsies and cytology to nonmalignant. Positive cytology was defined as diagnostic or strongly suspicious for malignancy. Inconclusive cytology, atypia, and dysplasia were not sufficient to designate a specimen positive for malignancy for either enrollment purposes or evaluation of response. After treatment discontinuation or complete response, cystoscopy and bladder wash cytology were performed quarterly for the first 2 years and semiannually after that. All histologic and cytologic interpretations were made at individual institutions; these constitute the basis of this report. Recurrence of papillary disease alone was not considered evidence of progressive disease if the lesions were resectable and histologically superficial (Stage Ta, TI ) and patients were allowed to continue treatment for CIS after resection of such tumors. Time to response or progression was measured from date of initial therapy to time of response or documented progression. Duration of response was measured from the date of complete response until either progression or latest time of evaluation. All patients were seen weekly for the first 4 weeks of therapy, monthly thereafter until withdrawn from treatment, and quarterly for 2 years after treatment. Required observations during therapy included assessment of symptoms of both disease and toxicity, complete blood counts, serum chemistries, and electrocardiograms. Holter monitoring was obtained in all 42 patients as described in the toxicity discussions of the Results section. Drug dosage was adjusted if toxicity was observed. Dose reductions preserved the treatment schedule of one dose every 2 hours for three doses daily for 3 days each week; each dose was decreased, and no doses were dropped. With resolution of toxicity, bropirimine was usually resumed at 50%, with resumption of full dose as allowed. Pharmacokinetic studies were performed in i6 cases at selected institutions and will be the subject of a later report. RESULTS Patient characteristics are summarized in Table I. T h i r t y - t h r e e ( 7 9 % ) o f 4 2 p a t i e n t s w e r e e v a l u a b l e for r e s p o n s e . F i v e w e r e d i s q u a l i f i e d d u e to l a c k of meeting entry criteria (all had recurrent Stage UROLOGY 48 (1), 1996
100
100-
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i
80 ¸
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: 60 4} o Im 4) o. 4 0
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a.
20 0
I
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'
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20I
!
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I
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I
6
12
18
24
30
36
Months
0
I
I
I
I
I
I
6
12
18
24
30
36
Months
FIGURE 1. Kaplan-Meier curve of intervals free of car-
FIGURE 2. Kaplan-Meier curve of intervals free of car-
cinoma in situ (ClS): 16 of 20 patients have been free of bladder CIS for intervals shown.
cinoma in situ (ClS) and papillary tumors: 14 of 20 patients have been free of bladder CIS or papillary tumors for intervals shown.
Ta or T1 tumor only without CIS immediately prior to entry), 2 were unevaluable due to lack of follow-up, and 2 dropped from the study early (at 3 weeks) due to toxicity. Twenty (61%) of 33 evaluable patients achieved a complete response of bladder CIS to bropirimine. Complete responses were seen in all categories when stratified according to prior therapy (Table II). Eight (67%) of 12 with no prior intravesical therapy responded, whereas 6 (67%) of 9 with prior intravesical chemotherapy did so. Two (29%) of 7 with prior BCG only and 4 (80%) of 5 with both prior BCG and prior intravesical chemotherapy had complete responses. Although small numbers preclude statistical comparison, no large differences in responses were seen between groups aged 70 years and older versus those younger than 70 or between those patients with unifocal versus multifocal CIS. Patients with primary CIS did have a higher response rate than those with secondary CIS (12 [80%] of 15 versus 8 [44%] of 18, respectively), a difference that approached but did not achieve statistical significance (P = 0.08, chi-square). Of the 20 complete responders, 4 patients have had a recurrence of CIS (between months 3 and 16), 1 received BCG percutaneously for uppertract CIS, one died while in remission, and 14 remain free of CIS (for 3 to 30 months). Thus, median duration of response has not been reached but exceeds 21 months (Fig. 1 ). Two patients who were complete responders developed recurrent Stage Ta lesions without associated CIS (Fig. 2). Eighteen patients had a history of papillary tumor associated with CIS, 10 in the 4 months immediately prior to study entry. Eight patients had a superficial tumor recurrence (5 with Stage Ta, 3 UROLOGY 48 (1), 1996
with Stage T1) during or after bropirimine therapy; a ninth had recurrence with progression from T1 at entry to T2 disease at month 3, the only patient with clinical evidence of progression to muscle invasion. The overall rate of stage progression to T2 was 3%. Toxicity (based on all 42 treated patients) at 3.0 g/day was modest and manageable. Significant toxicity had been seen at a higher dose in an earlier study that was stopped due to toxicity long before meeting its accrual goal. 24 That trial employed a total daily dose of 4.5 g in three divided doses of 1.5 g on a similar schedule as the trial reported herein. At that dosage, 9 (33%) of 27 patients dropped out from the study due to toxicity: 8 (30%) of 27 experienced grade 3 toxicity or greater, while only 4 (15%) of 27 experienced no toxicity. Chief among the toxicity seen at 4.5 g/ day were symptoms suggestive of interferon induction, including fever, chills, myalgia, arthralgia, and malaise. 2s Additionally, 8 patients noted tachycardia, chest pain, or palpitations; 2 had recognized myocardial infarctions; and 2 suffered unexplained sudden death. Dosage was therefore decreased to 3.0 g/day, Holter monitoring was instituted for all patients, and cardiac rhythm was recorded for 48 hours prior to the next scheduled treatment day and for 48 hours after treatment began. Following a negative evaluation, the 42-patient trial at 3.0 g/day was begun, with registrants undergoing 48 hours of pretherapy monitoring followed by 48 hours of monitoring on therapy. Thirty-nine patients had technically adequate pretreatment and treatment tapes. Average heart rates before and during treatment were 77.1 and 81.5 beats per minute, respectively. The average 23
TABLE
III.
Percent (%) of cases with any toxicity Grade
Headache Nausealemesis Fatigue/fever/chills/flu syndromelmalaiselmyalgia Increased SGOT or SGPT Arthralgialarthritis Rash/pruritus Urticaria Chest pain Sudden death Tachycardialpalpitations Diarrhea Abdominal pain Paresthesia Dysu rialcystitislhematuria
0
1
2
86 79 64 95 93 86 98 95 98 95 88 96 98 93
12 12 24 5 2 7
2 7 12
3
4
5
5 7 2
5 5 I0 2 2 2
2 2 5
KEY: S G O T = serum glutamic-oxaloacetic transaminase; S G P T = glutamic-pyruvic transaminase.
maximum heart rates observed before and during treatment were 133.7 and 141.5 beats per minute, respectively. Analysis of supraventricular tachydysrhythmias revealed similar frequencies and severity before and during treatment in 18 patients, decreases in 7, and increases in 14. Analysis of spontaneous ventricular arrythmias revealed similar frequencies. In 3 patients, junctional rhythm was found during treatment; in 1, pretreatment atrial flutter became atrial fibrillation during treatment. It was the opinion of three independent cardiology consultants that, at 3.0 g/day, the monitoring data did not suggest that bropirimine causes ventricular proarrhthymia or QT interval prolongation and that while the data did not exclude such a possibility, it also did not suggest such a possibility. It was noted that bropirimine might co-contribute to a small degree of depression in sinus node function, resulting in an increase in sinus bradycardia that was seen in two patients who also were taking concomitant medication known to cause such an effect. Neither of the two patients was symptomatic. At 3.0 g/day, only 2 (4%) of 42 patients experienced grade 3 or higher toxicity, and 15 (36%) of 42 experienced no toxicity at all. Possible cardiovascular events were seen in two patients with grade 1 chest pain and in two patients with grade 1 tachycardia or palpitations. One patient also suffered an unwitnessed sudden death several hours after bropirimine dosing during his 15th week of therapy. He had no history of cardiovascular problems and had experienced no cardiovascular symptoms on bropirimine to that point; his initial Holter recording prior to and during the first week of therapy had revealed no changes. Autopsy was 24
not performed, nor were electrocardiograms or cardiac enzyme level obtained. All symptoms listed in Table III were associated with the treatment period only; they were controlled in most cases with oral acetaminophen and in others by dose reduction. Elevations in liver enzymes were seen in 2 (5%) of 42 patients, with enzymes normalizing after the drug was stopped. Both patients resumed and continued at the 3.0 g/ day dose after enzyme normalization and did not experience repeat enzyme elevation. Rashes and/or pruritus occurred in 6 cases (14%). Rashes were not always pruritic; they disappeared upon discontinuation of therapy in all cases and, in all but one case, responded to symptomatic or prophylactic treatment with diphenhydramine (Benadryl) or terferradine (Seldane). In 3 cases (7%), polyarticular arthralgia not associated with a prior history of arthritis occurred during treatment; no etiology could be determined, but no patient discontinued therapy. Grade 1 or 2 diarrhea or abdominal pain occurred infrequently, with more frequent nausea seen. None discontinued therapy for these complaints. COMMENT These results confirm the efficacy of oral bropirimine against bladder CIS, using a dosage of 3.0 g/day on a divided repetitive schedule. Importantly, complete responses were seen in 50% of patients who had received prior BCG therapy, allowing some to avoid cystectomy for the duration of their responses. That an orally administered drug might achieve disease control at reasonable toxicity in 61% of previously untreated patients is also notable. Comparison of response rates acUROLOGY 48 (I), 1996
cording to prior BCG treatment is precluded due to the small size of the groups, but it is possible that failures to prior BCG treatment may not respond as well as previously untreated patients. Caution should be exercised in the interpretation that a response rate of 61% in previously untreated patients is less than that usually reported for BCG. The previously untreated patients represent only a fraction of the total patients in this Phase II trial; a Phase III comparison of bropirimine to BCG would be required for an accurate assessment of the differences between the drugs. Furthermore, only three published clinical trials, one using bropirimine and two using recombinant alpha interferon, have required positive cytology after biopsy to ensure that CIS was still present at the time of treatment. 23'26'27 No BCG trial to date has ever included this criterion, with the result that enrolled patients included a mixture of patients receiving BCG for therapy and others receiving it for prophylaxis; however, BCG data have always been reported as therapeutic response rates. Use of the same rigid requirement might decrease the BCG response rate for CIS to one similar to that of bropirimine in this study. Also, some patients with minimal CIS may have been excluded due to lower sensitivity of cytology in detecting small volume disease. The number of patients with CIS who were not enrolled due to negative cytology is not known. Bropirimine appears to have activity against multifocal as well as unifocal CIS. That a higher response rate was seen in patients with primary CIS (de novo and not associated with papillary disease) than in patients with secondary CIS (subsequent to or associated with papillary tumor [ s ] ) is not unexpected. However, small numbers prevent a statistically significant difference. More importantly, some patients with secondary or previously treated CIS may experience a complete response to bropirimine. The confirmation of clinically important responses to bropirimine as a single agent is very encouraging, albeit contradictory to preclinical in vivo laboratory studies. Sidky et al. 22 demonstrated significant dose-dependent decreases in subcutaneous MBT-2 tumors in C3H mice, but no impact on survival. Using intralesional injections, Simmons et al. 28 reported an antitumor effect approaching that of BCG, but no survival impact. In our initial laboratory studies, 21 we found also that bropirimine had no discernible single agent impact on survival. Regardless, the clinical benefit appears to be real, with a mean duration of response in excess of 21 months. Although the exact mechanism by which bropirimine exerts its anticancer effect is unknown, bropirimine-related immunomodulatory effects UROLOGY 48 (i), 1996
have been documented since its synthesis in 1980.19 Known as an interferon inducer, bropirimine possesses antiviral and antitumor activity, and it has antiproliferative activity in vitro at high concentrations that are not clinically achievable. Bropirimine can induce production of multiple cytokines in cultured h u m a n bladder cancer. 29 It potentiates cell-mediated cytotoxicity in multiple compartments, including the spleen, peritoneal exudate, lung, liver, peripheral blood, and bone marrow; this appears to be natural killer cell dependent as well as macrophage d e p e n d e n t ) ° Bropirimine-induced natural killer cell activation may occur in the absence of increased levels of serum interferon. 3° Thus, interferon induction by bropirimine may not be a requirement for bropirimine to be effective in CIS. Additional corroboration of the activity of bropirimine against CIS can be seen in a recent trial involving patients with CIS of the upper urinary tract. 31 In that study, patients with positive cytology from one or both radiographically negative upper urinary tracts received bropirimine at the same dose and schedule used in this trial for bladder CIS. Ten (48%) of 21 evaluable patients developed a negative cytology. Toxicity was similar; though follow-up was shorter than in this trial, responses with upper urinary tract CIS also appear to have some durability. The toxicity of bropirimine at 3.0 g/day appears to be tolerable, acceptable, and manageable. Many patients experienced no toxicity. Patients who experienced low-grade malaise and mild flu-like symptoms did so for approximately 24 hours after each dose. Fever was readily controlled by acetaminophen. Mild or moderate nausea and occasional emesis were reported, but were severe in only 2 cases, apparently related to the number of tablets ingested. Liver enzyme elevation may be related to hepatic glucuronidation, which accounts for the major metabolism of orally ingested bropirimine, but the mechanism is not clear. It is not known if pre-existing subclinical liver disease was present in these two patients. A relationship between bropirimine and cardiovascular side effects has not been excluded. Cardiovascular events were observed in 12 of 27 patients in the aborted trial at 4.5 g/day, nine of which were grade 3 or greater. In this trial at 3.0 g/day, four grade 1 events were seen, none resulting in dosage decrease or cessation of therapy; one unwitnessed sudden death occurred. Assessment of pre- and on-therapy Holter recordings from 39 cases at 3.0 g/day revealed no clinically relevant changes in rhythm or conduction associated with bropirimine treatment in 35; nonspecific changes in ventricular arrhythmia frequency or in degree of sinus bradycardia each occurred in 2 cases. M25
t h o u g h n o t a n a l y z e d in detail yet, m o r e t h a n 100 p a t i e n t s w i t h CIS h a v e s u b s e q u e n t l y r e c e i v e d b r o p i r i m i n e as s u b j e c t s in o t h e r trials at the s a m e d o s e and schedule. The only baseline exclusion cardiac c r i t e r i o n w a s the p r e s e n c e o f clinically significant c o n g e s t i v e h e a r t failure. T h e rate o f p r o g r e s s i o n to m u s c l e - i n v a s i v e disease w h i l e o n t h e r a p y w a s 3%. This is n o t u n e x p e c t e d for s u c h a h i g h - r i s k g r o u p in w h i c h 64% h a d a l r e a d y r e c e i v e d p r e v i o u s intravesical t h e r a p y , i n c l u d i n g 36% w h o h a d failed p r i o r B C G treatment. CONCLUSIONS Oral b r o p i r i m i n e has b e e n s h o w n to h a v e at least a m o d e r a t e level o f activity in the t r e a t m e n t o f b l a d d e r CIS, i n c l u d i n g s o m e p a t i e n t s w h o h a d failed p r i o r t h e r a p y w i t h BCG. W h e t h e r b r o p i r i m i n e finds a role as salvage for B C G failures or e v e n t u a l l y a s s u m e s a f r o n t - l i n e role w h i l e B C G is u s e d for b r o p i r i m i n e failures will h a v e to await the results of f u r t h e r clinical trials t h a t are u n d e r w a y . T h e p o t e n t i a l also exists for the use o f b o t h in c o m b i n a t i o n ; t h a t r e g i m e n c u r r e n t l y is u n d e r g o i n g P h a s e II e v a l u a t i o n in the S o u t h w e s t O n c o l o g y Group. ACKNOWLEDGMENT.To Brent Blumenstein, Ph.D., for his review of this manuscript. REFERENCES 1. Wingo PA, Tong T, and Bolden S: Cancer statistics, 1995. CA Cancer J Clin 45: 8-30~ 1995. 2. National Bladder Cancer Collaborative Group A ( N B C C G A ) : Surveillance, initial assessment, and subsequent progress of patients with superficial bladder cancer in a prospective longitudinal study. Cancer Res 37: 2907-2910, 1977. 3. Farrow GM, Utz DC, and Rife CC: Morphological and clinical observations of patients with early bladder cancer treated with total cystectomy. Cancer Res 36: 2495-2501, 1976. 4. Jewett HJ, and Strong GH: Infiltrating carcinoma of the bladder: relation of depth of penetration of the bladder wall to incidence of local extension and metastases. J Urol 55: 366-372, 1946. 5. Althausen AF, Prout GR, and Daly JJ: Non-invasive papillary carcinoma of the bladder associated with carcinoma in situ. J Urol 116: 575-580, 1976. 6. Raghavan D, Shipley WU, Garnick MB, Russell PJ, and Richie JP: Biology and management of bladder cancer. N Engl J Med 322: 1129-1138, 1990. 7. Farrow GM, Utz DC, Rife CC, and Greene LF: Clinical observations on sixty-nine cases of in situ carcinoma of the urinary bladder. Cancer Res 37: 2794-2798, 1977. 8. Sarosdy MF, and Lamm DL: Long-term results of intravesical Bacillus Calmette-Guerin therapy for superficial bladder carcinoma. J Urol 142: 719-722, 1989. 9. Lamm DL, Blumenstein BA, Crawford ED, Montie JE, Scardino P, Grossman HB, Stanisic TH, Smith JA Jr, Sullivan J, Sarosdy MF, et al: A randomized trial of intravesical doxorubicin and immunotherapy with Bacille Calmette-Guerin for 26
transitional-cell carcinoma of the bladder. N EnglJ Med 325: 1205-1209, 1991. 10. Morales A, NickelJC, and WilsonJWL: Dose-response of bacillus Calmette-Guerin in the treatment of superficial bladder cancer. J Urol 147: 1256-1258, 1992. 11. Nadler RB, Catalona WJ, Hudson MA, and Ratliff TL: Durability of the tumor-free response for intravesical bacillus Calmette-Guerin therapy. J Urol 152: 367-373, 1994. 12. Catalona WJ, Hudson MA, Gillen DP, Andriole GL, and Ratliff TL: Risks and benefits of repeated courses of intravesical bacillus Calmette-Guerin therapy for superficial bladder cancer. J Urol 137: 220-224, 1987. 13. Badalament RA, Herr HW, Wong GY, Gnecco C, Pinsky CM, Whitmore WF Jr, Fair WR, and Oettgen HF: A prospective randomized trial of maintenance versus nonmaintenance intravesical bacillus Calmette-Guerin therapy of superficial bladder cancer. J Clin Oncol 5: 441-449, 1987. 14. Brosman S: The influence of tice strain BCG treatment in patients with transitional cell carcinoma in situ. Prog Clin Biol Res 310: 193-205, 1989. 15. Lamm DL, Steg A, Boccon-Gibod L, Morales A, Hanna MG Jr, Pagano F, Alfthan O, Brosman S, Fisher HAF, Jakse G, et al: Complications of bacillus Calmette-Guerin immunotherapy: review of 2602 patients and comparison of chemotherapy complications. Prog Clin Biol Res 310: 335-355, 1989. 16. Rawls WH, Lamm DL, Lowe BA, Crawford ED, Sarosdy MF, Montie JE, Grossman HB, and Scardino PT: Fatal sepsis following intravesical BCG administration for bladder cancer: a Southwest Oncology Group study. J Urol 144: 1328-1330, 1990. 17. Lotzova E, Savary CA, and Stringfellow DA: 5-halo-6phenyl-pyrimidinones: new molecules with cancer chemotherapeutic potential and interferon-inducing capacity are strong inducers of murine natural killer cells. J Immuno1130: 965-969, 1983. 18. Lotzova E, Savary CA, Khan A, and Stringfellow DA: Stimulation of natural killer cells in two random-bred strains of athymic rats by interferon-inducing pyrimidinone. J lmmunol 132: 2566-2570, 1984. 19. Wierenga W: Antiviral and other bioactivities of pyrimidinones. Pharmacol Ther 30: 67-89, 1985. 20. Tracey DE, and Richard KA: Mechanisms of immunostimulation by pyrimidinones. Prog Leukocyte Biol 6: 279289, 1987. 21. Sarosdy MF, and Kierum CA: Combination immunotherapy of murine transitional cell cancer using BCG and an interferon-inducing pyrimidinone. J Urol 142: 1376-1379, 1989. 22. Sidky YA, Borden EC, Wierenga W, and Bryan GT: Inhibitory effects of interferon-inducing pyrimidinones on the growth of transplantable mouse bladder tumors. Cancer Res 46: 3798-3802, 1986. 23. Sarosdy MF, Lamm DL, Williams RD, Moon TD, Flanigan RC, Crawford ED, Wilks NE, Earhart RH, and Merritt JA: Phase I trial of oral bropirimine in superficial bladder cancer. J Urol 147: 31-33, 1992. 24. Sarosdy MF, Lowe BA, Schellhammer PF, Lamm DL, Graham SD Jr, Grossman HB, See WA, Peabody JO, Moon TD, Flanigan RC, et al: Bropirimine immunotherapy of bladder CIS: positive phase II results of an oral interferon inducer. Proc Annu Meet Am Soc Clin Oncol 13: A719, 1994. 25. Spiegel RJ: The alpha interferons: clinical overview. Semin Oncol 14(suppl 2):1-12, 1987. 26. Torti FM, Shortliffe LD, Williams RD, Pitts WC, Kempson RL, Ross JC, Palmer J, Meyers F, Ferrari M, Hannigan J, et al: Alpha-interferon in superficial bladder cancer: a UROLOGY 48 (1), 1996
Northern California Oncology Group study. J Clin Oncol 6: 476-483, 1988. 27. Williams R, Sarosdy M, Catalona W, Chodak G, Vogelsang N, Freika F, and Torti F: Randomized trial of high vs. low dose intravesical interferon alpha 2-B (IFN-a2/3) treatment of bladder carcinoma in situ (CIS). Proc Am Soc Clin Oncol 7: 121, 1988. 28. Simmons WB, Reichert DF, Lucio RM, and Lamm DL: Pyrimidinone interferon inducers in the treatment of murine transitional cell carcinoma. Proceedings of the 78th Annual Meeting of the American Urological Association, Las Vegas, Nevada, 1983, p 169.
UROLOGY 48 (1), 1996
29. Kita M, Tong LJ, and Imanishi J: Induction of IFN-c~, IL-lfl, and TNF-~ mRNA by bropirimine in human bladder cancer cells. Igaku no Ayumi 169: 307-308, 1994. 30. Li LH, Wallace TL, Hamilton RD, and DeKoning TF: Relationship between activation of natural killer cell activity and antitumor activity of pyrimidinones, in Schmidt RE, (Ed): Natural Killer Cells: Biology and Clinical. Basel, Karger, 1990, pp 248-253. 31. Sarosdy MF, Pisters LL, Carroll PR, Benson MC, Moon TD, Lamm DL, Hudson MA, Lerner SP, Koch MO, and Schellhammer PF: Bropirimine immunotherapy of upper urinary tract carcinoma in situ. Urology 48: 28-32, 1996.
27
ELSEVIER
ORAL BROPIRIMINE IMMUNOTHERAPY OF CARCINOMA IN SITU OF THE BLADDER: RESULTS OF A PHASE II TRIAL MICHAEL F. SAROSDY, BRUCE A. LOWE, PAUL F. SCHELLHAMMER, DONALD L. LAMM, SAM D. GRAHAM, JR., H. BARTON GROSSMAN, WILLIAM A. SEE, JAMES O. PEABODY, TIMOTHY D. MOON, ROBERT C. FLANIGAN, E. DAVID CRAWFORD, AND JOEL MORGANROTH
ABSTRACT Objectives. Bropirimine is an orally administered immunostimulant that has been shown to have activity against carcinoma in situ (CIS) of the bladder. To further assess this potential activity, bropirimine was administered to 42 patients for bladder CIS in a Phase II trial. Methods. Patients were treated with bropirimine 3.0 g/day by mouth for 3 consecutive days each week up to I year. Cystoscopy with biopsies and bladder wash cytology were performed quarterly. Results. Twenty (61%) of 33 evaluable patients converted malignant biopsies and bladder wash cytology to negative, including 6 (50%) of 12 who failed prior bacillus Calmette-Gu6rin (BCG) immunotherapy, 14 (67%) of 21 who had not received prior BCG therapy, and 12 (80%) of 15 with primary CIS. Median response duration exceeds 21 months. Four of the 20 responders did have a papillary tumor recurrence at 3 to I S months, all Stage Ta or TI. Mild toxicity (grade I or II) suggestive of interferon induction or administration occurred in one third of patients. Headache, transient hepatic enzyme elevations, skin rash, and arthralgias each occurred in 5% to 14% of the patients, with nausea or emesis in 21%. Grade i tachycardialpalpitations or chest pain each were noted in 5%. Conclusions. Oral bropirimine can induce remission of bladder CIS with acceptable toxicity at 3.0 g/day. Bropirimine may be a valuable alternative to cystectomy for some failures of BCG therapy and may have the potential to replace BCG as frontline therapy because of its ease of administration. UROLOGY 48: 21-27, 1996.
arcinoma in situ (CIS) of the bladder is a high-grade intraepithelial cancer that occurs C as an isolated lesion or coexists with papillary tumors in 10% to 20% of cases of bladder can-
From the Departments of Urology: University of Texas Health Science Center, San Antonio, Texas; Oregon Health Science University, Portland, Oregon; Eastern Virginia Medical School, Norfolk, Virginia; West Virginia University, Morgantown, West Virginia; Emory Clinic, Atlanta, Georgia; University of Michigan, Ann Arbor, Michigan; University of Iowa Hospital and Clinic, Iowa City, Iowa; Henry Ford Hospital, Detroit, Michigan; University of Wisconsin Hospital and Clinic, Madison, Wisconsin; Loyola University Medical Center, Maywood, Illinois; and University of Colorado Health Sciences Center, Denver, Colorado; and the Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania Present address of H. Barton Grossman is University of Texas, M.D, Anderson Cancer Center, Houston, Texas Reprint requests: Michael F. Sarosdy, M.D., Division of Urology, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78284-7845 Submitted: January 9, 1996, accepted (with revisions): March 11, 1996 COPYRIGHT 1996 BY ELSEVIER SCIENCE INC. ALL RIGHTS RESERVED
cer. 1-7 Intravesical i m m u n o t h e r a p y with bacillus Calmette-Gu~rin (BCG) has efficacy against superficial bladder cancer and is also the drug of choice for the treatment of CIS; it was approved by the Food and Drug Administration (FDA) in 1990. 8.9 However, controversy remains regarding the optimal duration and n u m b e r of treatments. It is clear that not all patients respond to BCG and that some who do respond will eventually relapse. ~°-14 Toxicity of intravesical BCG can be substantial, and treatment-related fatalities have occurred.15'~6 Alternative treatments for bladder CIS are needed. Bropirimine ( 2 - a m i n o - 5 - b r o m o - 6 - p h e n y l - 4 (3H)-pyrimidinone; Pharmacia & Upjohn, Inc., Kalamazoo, Mich) is an orally active immunomodulator that increases endogenous alpha-interferon and other cytokines; it also activates several cell-mediated immunologic defense mechanisms. 17-2° Based upon in vivo laboratory studies, 21,= a pilot trial of bropirimine was performed in patients with superficial bladder cancer. That 0090-4295/96/$15.00 PII S 0 0 9 0 - 4 2 9 5 ( 9 6 ) 0 0 0 5 9 - 3
21
TABLE I.
Patient characteristics
Age (years) Sex Male Female Southwest Oncology Group performance status (all patients) 0 1 2 Type of carcinoma in situ Primary Secondary Unifocal Multi focal *
37-81 (median 68) 38
4
35 5 2 15 18 8 25
Evaluable patients only.
TABLE
Completeresponse by prognostic factors
II.
Age ->70 years Age <70 years Primary CIS Secondary CIS Unifocal CIS Multifocal CIS Prior therapy None Prior chemotherapy only Prior BCG only Prior chemotherapy and BCG
11117 (65%) 9/16 (56%) 12115 (80%) 8/18 (44%) 6/8 (75%) 14/25 (56%} 8/12 6/9 2/7 4/5
(67%) (67%) (29%) (80%)
KEy: CIS = carcinoma in situ; BCG = bacillus Calmette-Ga~rin.
study indicated activity of bropirimine, chiefly in CIS. z3 E f f i c a c y w a s n o t e d b o t h i n p a t i e n t s w h o h a d previously been treated with BCG or intravesical i n t e r f e r o n , as w e l l as i n p a t i e n t s n o t p r e v i o u s l y treated. To confirm and further assess this activity, a m u l t i c e n t e r P h a s e II t r i a l o f o r a l b r o p i r i m i n e i n p a t i e n t s w i t h CIS o f t h e b l a d d e r w a s u n d e r t a k e n . MATERIAL
AND METHODS
The trial was a multicenter phase II study. Patients were required to have pathologically proven CIS without muscleinvasive disease, as well as six-site bladder and prostatic urethral biopsy mapping within 4 weeks of registration. Patients with concomitant papillary tumor (s) were eligible only if the papillary tumor (s) had been resected. A cytologicallypositive bladder wash obtained at least 24 hours after biopsy was required to confirm the continued presence of CIS. Patients with a prostatic urethral biopsy positive for CIS were eligible, and all patients were eligible regardless of prior therapy unless that included bropirimine. Patients were categorized as having CIS alone or in conjunction with resected papillary Stage Ta or T 1 tumors. Other descriptors included extent of bladder involvement (unifocal/multifocal), prior intravesical therapy 2:2
(none, BCG, or chemotherapy), and primary versus secondary C1S. Patients were required to have a Southwest Oncology Group performance status of 0 to 2, and normal liver, renal, and hematologic functions. All patients gave written informed consent. Bropirimine was formulated in compressed tablets containing 250 mg micronized nonhygroscopic drug. Dosing was initiated at least 1 week after bladder biopsies and after gross hematuria had cleared. Patients received oral bropirimine 3.0 g/day each evening for three consecutive nights weekly for 12 weeks. The total daily dose was divided into three equal fractions ( 1.0 g each) administered at 2-hour intervals (based upon previous pharmacokinetic studies) and self-administered on an outpatient basis. Compliance was assessed by comparison of dispensed and returned pill counts for each patient. Patients tolerating therapy were treated for 12 consecutive weeks followed by cystoscopy, bladder biopsies, and bladder wash cytology. Patients with progressive disease (Stage T2 or greater) were removed from the study. Patients with stable disease (no change) at I2 weeks were allowed to continue therapy for an additional 12 weeks, with subsequent identical re-evaluation. Patients who had a complete response at either 12 or 24 weeks were allowed to complete 1 year of therapy, at which time bropirimine was discontinued. Complete response was defined as conversion of biopsies and cytology to nonmalignant. Positive cytology was defined as diagnostic or strongly suspicious for malignancy. Inconclusive cytology, atypia, and dysplasia were not sufficient to designate a specimen positive for malignancy for either enrollment purposes or evaluation of response. After treatment discontinuation or complete response, cystoscopy and bladder wash cytology were performed quarterly for the first 2 years and semiannually after that. All histologic and cytologic interpretations were made at individual institutions; these constitute the basis of this report. Recurrence of papillary disease alone was not considered evidence of progressive disease if the lesions were resectable and histologically superficial (Stage Ta, TI ) and patients were allowed to continue treatment for CIS after resection of such tumors. Time to response or progression was measured from date of initial therapy to time of response or documented progression. Duration of response was measured from the date of complete response until either progression or latest time of evaluation. All patients were seen weekly for the first 4 weeks of therapy, monthly thereafter until withdrawn from treatment, and quarterly for 2 years after treatment. Required observations during therapy included assessment of symptoms of both disease and toxicity, complete blood counts, serum chemistries, and electrocardiograms. Holter monitoring was obtained in all 42 patients as described in the toxicity discussions of the Results section. Drug dosage was adjusted if toxicity was observed. Dose reductions preserved the treatment schedule of one dose every 2 hours for three doses daily for 3 days each week; each dose was decreased, and no doses were dropped. With resolution of toxicity, bropirimine was usually resumed at 50%, with resumption of full dose as allowed. Pharmacokinetic studies were performed in i6 cases at selected institutions and will be the subject of a later report. RESULTS Patient characteristics are summarized in Table I. T h i r t y - t h r e e ( 7 9 % ) o f 4 2 p a t i e n t s w e r e e v a l u a b l e for r e s p o n s e . F i v e w e r e d i s q u a l i f i e d d u e to l a c k of meeting entry criteria (all had recurrent Stage UROLOGY 48 (1), 1996
100
100-
i,
i
80 ¸
II
I
•
I
i i
i
i
"
I
I
II
," 60-
: 60 4} o Im 4) o. 4 0
o Q i._
a.
20 0
I
80.
'
40-
20I
!
I
I
I
I
6
12
18
24
30
36
Months
0
I
I
I
I
I
I
6
12
18
24
30
36
Months
FIGURE 1. Kaplan-Meier curve of intervals free of car-
FIGURE 2. Kaplan-Meier curve of intervals free of car-
cinoma in situ (ClS): 16 of 20 patients have been free of bladder CIS for intervals shown.
cinoma in situ (ClS) and papillary tumors: 14 of 20 patients have been free of bladder CIS or papillary tumors for intervals shown.
Ta or T1 tumor only without CIS immediately prior to entry), 2 were unevaluable due to lack of follow-up, and 2 dropped from the study early (at 3 weeks) due to toxicity. Twenty (61%) of 33 evaluable patients achieved a complete response of bladder CIS to bropirimine. Complete responses were seen in all categories when stratified according to prior therapy (Table II). Eight (67%) of 12 with no prior intravesical therapy responded, whereas 6 (67%) of 9 with prior intravesical chemotherapy did so. Two (29%) of 7 with prior BCG only and 4 (80%) of 5 with both prior BCG and prior intravesical chemotherapy had complete responses. Although small numbers preclude statistical comparison, no large differences in responses were seen between groups aged 70 years and older versus those younger than 70 or between those patients with unifocal versus multifocal CIS. Patients with primary CIS did have a higher response rate than those with secondary CIS (12 [80%] of 15 versus 8 [44%] of 18, respectively), a difference that approached but did not achieve statistical significance (P = 0.08, chi-square). Of the 20 complete responders, 4 patients have had a recurrence of CIS (between months 3 and 16), 1 received BCG percutaneously for uppertract CIS, one died while in remission, and 14 remain free of CIS (for 3 to 30 months). Thus, median duration of response has not been reached but exceeds 21 months (Fig. 1 ). Two patients who were complete responders developed recurrent Stage Ta lesions without associated CIS (Fig. 2). Eighteen patients had a history of papillary tumor associated with CIS, 10 in the 4 months immediately prior to study entry. Eight patients had a superficial tumor recurrence (5 with Stage Ta, 3 UROLOGY 48 (1), 1996
with Stage T1) during or after bropirimine therapy; a ninth had recurrence with progression from T1 at entry to T2 disease at month 3, the only patient with clinical evidence of progression to muscle invasion. The overall rate of stage progression to T2 was 3%. Toxicity (based on all 42 treated patients) at 3.0 g/day was modest and manageable. Significant toxicity had been seen at a higher dose in an earlier study that was stopped due to toxicity long before meeting its accrual goal. 24 That trial employed a total daily dose of 4.5 g in three divided doses of 1.5 g on a similar schedule as the trial reported herein. At that dosage, 9 (33%) of 27 patients dropped out from the study due to toxicity: 8 (30%) of 27 experienced grade 3 toxicity or greater, while only 4 (15%) of 27 experienced no toxicity. Chief among the toxicity seen at 4.5 g/ day were symptoms suggestive of interferon induction, including fever, chills, myalgia, arthralgia, and malaise. 2s Additionally, 8 patients noted tachycardia, chest pain, or palpitations; 2 had recognized myocardial infarctions; and 2 suffered unexplained sudden death. Dosage was therefore decreased to 3.0 g/day, Holter monitoring was instituted for all patients, and cardiac rhythm was recorded for 48 hours prior to the next scheduled treatment day and for 48 hours after treatment began. Following a negative evaluation, the 42-patient trial at 3.0 g/day was begun, with registrants undergoing 48 hours of pretherapy monitoring followed by 48 hours of monitoring on therapy. Thirty-nine patients had technically adequate pretreatment and treatment tapes. Average heart rates before and during treatment were 77.1 and 81.5 beats per minute, respectively. The average 23
TABLE
III.
Percent (%) of cases with any toxicity Grade
Headache Nausealemesis Fatigue/fever/chills/flu syndromelmalaiselmyalgia Increased SGOT or SGPT Arthralgialarthritis Rash/pruritus Urticaria Chest pain Sudden death Tachycardialpalpitations Diarrhea Abdominal pain Paresthesia Dysu rialcystitislhematuria
0
1
2
86 79 64 95 93 86 98 95 98 95 88 96 98 93
12 12 24 5 2 7
2 7 12
3
4
5
5 7 2
5 5 I0 2 2 2
2 2 5
KEY: S G O T = serum glutamic-oxaloacetic transaminase; S G P T = glutamic-pyruvic transaminase.
maximum heart rates observed before and during treatment were 133.7 and 141.5 beats per minute, respectively. Analysis of supraventricular tachydysrhythmias revealed similar frequencies and severity before and during treatment in 18 patients, decreases in 7, and increases in 14. Analysis of spontaneous ventricular arrythmias revealed similar frequencies. In 3 patients, junctional rhythm was found during treatment; in 1, pretreatment atrial flutter became atrial fibrillation during treatment. It was the opinion of three independent cardiology consultants that, at 3.0 g/day, the monitoring data did not suggest that bropirimine causes ventricular proarrhthymia or QT interval prolongation and that while the data did not exclude such a possibility, it also did not suggest such a possibility. It was noted that bropirimine might co-contribute to a small degree of depression in sinus node function, resulting in an increase in sinus bradycardia that was seen in two patients who also were taking concomitant medication known to cause such an effect. Neither of the two patients was symptomatic. At 3.0 g/day, only 2 (4%) of 42 patients experienced grade 3 or higher toxicity, and 15 (36%) of 42 experienced no toxicity at all. Possible cardiovascular events were seen in two patients with grade 1 chest pain and in two patients with grade 1 tachycardia or palpitations. One patient also suffered an unwitnessed sudden death several hours after bropirimine dosing during his 15th week of therapy. He had no history of cardiovascular problems and had experienced no cardiovascular symptoms on bropirimine to that point; his initial Holter recording prior to and during the first week of therapy had revealed no changes. Autopsy was 24
not performed, nor were electrocardiograms or cardiac enzyme level obtained. All symptoms listed in Table III were associated with the treatment period only; they were controlled in most cases with oral acetaminophen and in others by dose reduction. Elevations in liver enzymes were seen in 2 (5%) of 42 patients, with enzymes normalizing after the drug was stopped. Both patients resumed and continued at the 3.0 g/ day dose after enzyme normalization and did not experience repeat enzyme elevation. Rashes and/or pruritus occurred in 6 cases (14%). Rashes were not always pruritic; they disappeared upon discontinuation of therapy in all cases and, in all but one case, responded to symptomatic or prophylactic treatment with diphenhydramine (Benadryl) or terferradine (Seldane). In 3 cases (7%), polyarticular arthralgia not associated with a prior history of arthritis occurred during treatment; no etiology could be determined, but no patient discontinued therapy. Grade 1 or 2 diarrhea or abdominal pain occurred infrequently, with more frequent nausea seen. None discontinued therapy for these complaints. COMMENT These results confirm the efficacy of oral bropirimine against bladder CIS, using a dosage of 3.0 g/day on a divided repetitive schedule. Importantly, complete responses were seen in 50% of patients who had received prior BCG therapy, allowing some to avoid cystectomy for the duration of their responses. That an orally administered drug might achieve disease control at reasonable toxicity in 61% of previously untreated patients is also notable. Comparison of response rates acUROLOGY 48 (I), 1996
cording to prior BCG treatment is precluded due to the small size of the groups, but it is possible that failures to prior BCG treatment may not respond as well as previously untreated patients. Caution should be exercised in the interpretation that a response rate of 61% in previously untreated patients is less than that usually reported for BCG. The previously untreated patients represent only a fraction of the total patients in this Phase II trial; a Phase III comparison of bropirimine to BCG would be required for an accurate assessment of the differences between the drugs. Furthermore, only three published clinical trials, one using bropirimine and two using recombinant alpha interferon, have required positive cytology after biopsy to ensure that CIS was still present at the time of treatment. 23'26'27 No BCG trial to date has ever included this criterion, with the result that enrolled patients included a mixture of patients receiving BCG for therapy and others receiving it for prophylaxis; however, BCG data have always been reported as therapeutic response rates. Use of the same rigid requirement might decrease the BCG response rate for CIS to one similar to that of bropirimine in this study. Also, some patients with minimal CIS may have been excluded due to lower sensitivity of cytology in detecting small volume disease. The number of patients with CIS who were not enrolled due to negative cytology is not known. Bropirimine appears to have activity against multifocal as well as unifocal CIS. That a higher response rate was seen in patients with primary CIS (de novo and not associated with papillary disease) than in patients with secondary CIS (subsequent to or associated with papillary tumor [ s ] ) is not unexpected. However, small numbers prevent a statistically significant difference. More importantly, some patients with secondary or previously treated CIS may experience a complete response to bropirimine. The confirmation of clinically important responses to bropirimine as a single agent is very encouraging, albeit contradictory to preclinical in vivo laboratory studies. Sidky et al. 22 demonstrated significant dose-dependent decreases in subcutaneous MBT-2 tumors in C3H mice, but no impact on survival. Using intralesional injections, Simmons et al. 28 reported an antitumor effect approaching that of BCG, but no survival impact. In our initial laboratory studies, 21 we found also that bropirimine had no discernible single agent impact on survival. Regardless, the clinical benefit appears to be real, with a mean duration of response in excess of 21 months. Although the exact mechanism by which bropirimine exerts its anticancer effect is unknown, bropirimine-related immunomodulatory effects UROLOGY 48 (i), 1996
have been documented since its synthesis in 1980.19 Known as an interferon inducer, bropirimine possesses antiviral and antitumor activity, and it has antiproliferative activity in vitro at high concentrations that are not clinically achievable. Bropirimine can induce production of multiple cytokines in cultured h u m a n bladder cancer. 29 It potentiates cell-mediated cytotoxicity in multiple compartments, including the spleen, peritoneal exudate, lung, liver, peripheral blood, and bone marrow; this appears to be natural killer cell dependent as well as macrophage d e p e n d e n t ) ° Bropirimine-induced natural killer cell activation may occur in the absence of increased levels of serum interferon. 3° Thus, interferon induction by bropirimine may not be a requirement for bropirimine to be effective in CIS. Additional corroboration of the activity of bropirimine against CIS can be seen in a recent trial involving patients with CIS of the upper urinary tract. 31 In that study, patients with positive cytology from one or both radiographically negative upper urinary tracts received bropirimine at the same dose and schedule used in this trial for bladder CIS. Ten (48%) of 21 evaluable patients developed a negative cytology. Toxicity was similar; though follow-up was shorter than in this trial, responses with upper urinary tract CIS also appear to have some durability. The toxicity of bropirimine at 3.0 g/day appears to be tolerable, acceptable, and manageable. Many patients experienced no toxicity. Patients who experienced low-grade malaise and mild flu-like symptoms did so for approximately 24 hours after each dose. Fever was readily controlled by acetaminophen. Mild or moderate nausea and occasional emesis were reported, but were severe in only 2 cases, apparently related to the number of tablets ingested. Liver enzyme elevation may be related to hepatic glucuronidation, which accounts for the major metabolism of orally ingested bropirimine, but the mechanism is not clear. It is not known if pre-existing subclinical liver disease was present in these two patients. A relationship between bropirimine and cardiovascular side effects has not been excluded. Cardiovascular events were observed in 12 of 27 patients in the aborted trial at 4.5 g/day, nine of which were grade 3 or greater. In this trial at 3.0 g/day, four grade 1 events were seen, none resulting in dosage decrease or cessation of therapy; one unwitnessed sudden death occurred. Assessment of pre- and on-therapy Holter recordings from 39 cases at 3.0 g/day revealed no clinically relevant changes in rhythm or conduction associated with bropirimine treatment in 35; nonspecific changes in ventricular arrhythmia frequency or in degree of sinus bradycardia each occurred in 2 cases. M25
t h o u g h n o t a n a l y z e d in detail yet, m o r e t h a n 100 p a t i e n t s w i t h CIS h a v e s u b s e q u e n t l y r e c e i v e d b r o p i r i m i n e as s u b j e c t s in o t h e r trials at the s a m e d o s e and schedule. The only baseline exclusion cardiac c r i t e r i o n w a s the p r e s e n c e o f clinically significant c o n g e s t i v e h e a r t failure. T h e rate o f p r o g r e s s i o n to m u s c l e - i n v a s i v e disease w h i l e o n t h e r a p y w a s 3%. This is n o t u n e x p e c t e d for s u c h a h i g h - r i s k g r o u p in w h i c h 64% h a d a l r e a d y r e c e i v e d p r e v i o u s intravesical t h e r a p y , i n c l u d i n g 36% w h o h a d failed p r i o r B C G treatment. CONCLUSIONS Oral b r o p i r i m i n e has b e e n s h o w n to h a v e at least a m o d e r a t e level o f activity in the t r e a t m e n t o f b l a d d e r CIS, i n c l u d i n g s o m e p a t i e n t s w h o h a d failed p r i o r t h e r a p y w i t h BCG. W h e t h e r b r o p i r i m i n e finds a role as salvage for B C G failures or e v e n t u a l l y a s s u m e s a f r o n t - l i n e role w h i l e B C G is u s e d for b r o p i r i m i n e failures will h a v e to await the results of f u r t h e r clinical trials t h a t are u n d e r w a y . T h e p o t e n t i a l also exists for the use o f b o t h in c o m b i n a t i o n ; t h a t r e g i m e n c u r r e n t l y is u n d e r g o i n g P h a s e II e v a l u a t i o n in the S o u t h w e s t O n c o l o g y Group. ACKNOWLEDGMENT.To Brent Blumenstein, Ph.D., for his review of this manuscript. REFERENCES 1. Wingo PA, Tong T, and Bolden S: Cancer statistics, 1995. CA Cancer J Clin 45: 8-30~ 1995. 2. National Bladder Cancer Collaborative Group A ( N B C C G A ) : Surveillance, initial assessment, and subsequent progress of patients with superficial bladder cancer in a prospective longitudinal study. Cancer Res 37: 2907-2910, 1977. 3. Farrow GM, Utz DC, and Rife CC: Morphological and clinical observations of patients with early bladder cancer treated with total cystectomy. Cancer Res 36: 2495-2501, 1976. 4. Jewett HJ, and Strong GH: Infiltrating carcinoma of the bladder: relation of depth of penetration of the bladder wall to incidence of local extension and metastases. J Urol 55: 366-372, 1946. 5. Althausen AF, Prout GR, and Daly JJ: Non-invasive papillary carcinoma of the bladder associated with carcinoma in situ. J Urol 116: 575-580, 1976. 6. Raghavan D, Shipley WU, Garnick MB, Russell PJ, and Richie JP: Biology and management of bladder cancer. N Engl J Med 322: 1129-1138, 1990. 7. Farrow GM, Utz DC, Rife CC, and Greene LF: Clinical observations on sixty-nine cases of in situ carcinoma of the urinary bladder. Cancer Res 37: 2794-2798, 1977. 8. Sarosdy MF, and Lamm DL: Long-term results of intravesical Bacillus Calmette-Guerin therapy for superficial bladder carcinoma. J Urol 142: 719-722, 1989. 9. Lamm DL, Blumenstein BA, Crawford ED, Montie JE, Scardino P, Grossman HB, Stanisic TH, Smith JA Jr, Sullivan J, Sarosdy MF, et al: A randomized trial of intravesical doxorubicin and immunotherapy with Bacille Calmette-Guerin for 26
transitional-cell carcinoma of the bladder. N EnglJ Med 325: 1205-1209, 1991. 10. Morales A, NickelJC, and WilsonJWL: Dose-response of bacillus Calmette-Guerin in the treatment of superficial bladder cancer. J Urol 147: 1256-1258, 1992. 11. Nadler RB, Catalona WJ, Hudson MA, and Ratliff TL: Durability of the tumor-free response for intravesical bacillus Calmette-Guerin therapy. J Urol 152: 367-373, 1994. 12. Catalona WJ, Hudson MA, Gillen DP, Andriole GL, and Ratliff TL: Risks and benefits of repeated courses of intravesical bacillus Calmette-Guerin therapy for superficial bladder cancer. J Urol 137: 220-224, 1987. 13. Badalament RA, Herr HW, Wong GY, Gnecco C, Pinsky CM, Whitmore WF Jr, Fair WR, and Oettgen HF: A prospective randomized trial of maintenance versus nonmaintenance intravesical bacillus Calmette-Guerin therapy of superficial bladder cancer. J Clin Oncol 5: 441-449, 1987. 14. Brosman S: The influence of tice strain BCG treatment in patients with transitional cell carcinoma in situ. Prog Clin Biol Res 310: 193-205, 1989. 15. Lamm DL, Steg A, Boccon-Gibod L, Morales A, Hanna MG Jr, Pagano F, Alfthan O, Brosman S, Fisher HAF, Jakse G, et al: Complications of bacillus Calmette-Guerin immunotherapy: review of 2602 patients and comparison of chemotherapy complications. Prog Clin Biol Res 310: 335-355, 1989. 16. Rawls WH, Lamm DL, Lowe BA, Crawford ED, Sarosdy MF, Montie JE, Grossman HB, and Scardino PT: Fatal sepsis following intravesical BCG administration for bladder cancer: a Southwest Oncology Group study. J Urol 144: 1328-1330, 1990. 17. Lotzova E, Savary CA, and Stringfellow DA: 5-halo-6phenyl-pyrimidinones: new molecules with cancer chemotherapeutic potential and interferon-inducing capacity are strong inducers of murine natural killer cells. J Immuno1130: 965-969, 1983. 18. Lotzova E, Savary CA, Khan A, and Stringfellow DA: Stimulation of natural killer cells in two random-bred strains of athymic rats by interferon-inducing pyrimidinone. J lmmunol 132: 2566-2570, 1984. 19. Wierenga W: Antiviral and other bioactivities of pyrimidinones. Pharmacol Ther 30: 67-89, 1985. 20. Tracey DE, and Richard KA: Mechanisms of immunostimulation by pyrimidinones. Prog Leukocyte Biol 6: 279289, 1987. 21. Sarosdy MF, and Kierum CA: Combination immunotherapy of murine transitional cell cancer using BCG and an interferon-inducing pyrimidinone. J Urol 142: 1376-1379, 1989. 22. Sidky YA, Borden EC, Wierenga W, and Bryan GT: Inhibitory effects of interferon-inducing pyrimidinones on the growth of transplantable mouse bladder tumors. Cancer Res 46: 3798-3802, 1986. 23. Sarosdy MF, Lamm DL, Williams RD, Moon TD, Flanigan RC, Crawford ED, Wilks NE, Earhart RH, and Merritt JA: Phase I trial of oral bropirimine in superficial bladder cancer. J Urol 147: 31-33, 1992. 24. Sarosdy MF, Lowe BA, Schellhammer PF, Lamm DL, Graham SD Jr, Grossman HB, See WA, Peabody JO, Moon TD, Flanigan RC, et al: Bropirimine immunotherapy of bladder CIS: positive phase II results of an oral interferon inducer. Proc Annu Meet Am Soc Clin Oncol 13: A719, 1994. 25. Spiegel RJ: The alpha interferons: clinical overview. Semin Oncol 14(suppl 2):1-12, 1987. 26. Torti FM, Shortliffe LD, Williams RD, Pitts WC, Kempson RL, Ross JC, Palmer J, Meyers F, Ferrari M, Hannigan J, et al: Alpha-interferon in superficial bladder cancer: a UROLOGY 48 (1), 1996
Northern California Oncology Group study. J Clin Oncol 6: 476-483, 1988. 27. Williams R, Sarosdy M, Catalona W, Chodak G, Vogelsang N, Freika F, and Torti F: Randomized trial of high vs. low dose intravesical interferon alpha 2-B (IFN-a2/3) treatment of bladder carcinoma in situ (CIS). Proc Am Soc Clin Oncol 7: 121, 1988. 28. Simmons WB, Reichert DF, Lucio RM, and Lamm DL: Pyrimidinone interferon inducers in the treatment of murine transitional cell carcinoma. Proceedings of the 78th Annual Meeting of the American Urological Association, Las Vegas, Nevada, 1983, p 169.
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29. Kita M, Tong LJ, and Imanishi J: Induction of IFN-c~, IL-lfl, and TNF-~ mRNA by bropirimine in human bladder cancer cells. Igaku no Ayumi 169: 307-308, 1994. 30. Li LH, Wallace TL, Hamilton RD, and DeKoning TF: Relationship between activation of natural killer cell activity and antitumor activity of pyrimidinones, in Schmidt RE, (Ed): Natural Killer Cells: Biology and Clinical. Basel, Karger, 1990, pp 248-253. 31. Sarosdy MF, Pisters LL, Carroll PR, Benson MC, Moon TD, Lamm DL, Hudson MA, Lerner SP, Koch MO, and Schellhammer PF: Bropirimine immunotherapy of upper urinary tract carcinoma in situ. Urology 48: 28-32, 1996.
27