ELEVATED PROSTATE SPECIFIC ANTIGEN SERUM LEVELS AFTER INTRAVESICAL INSTILLATION OF BACILLUS CALMETTE-GUERIN

0022-5347/00/1645-1546/0 THE JOURNAL OF UROLOGY® Copyright © 2000 by AMERICAN UROLOGICAL ASSOCIATION, INC.®

Vol. 164, 1546 –1549, November 2000 Printed in U.S.A.

ELEVATED PROSTATE SPECIFIC ANTIGEN SERUM LEVELS AFTER INTRAVESICAL INSTILLATION OF BACILLUS CALMETTE-GUERIN DAN LEIBOVICI, AMNON ZISMAN, ZEHAVA CHEN-LEVYI, HELIO CYPELE, YORAM I. SIEGEL, SHLOMO FAITELOVICH AND ARIE LINDNER From the Department of Urology and Laboratory of Biochemistry, Assaf-Harofe Medical Center, Zerifin and Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel

ABSTRACT

Purpose: We determined whether intravesical bacillus Calmette-Guerin (BCG) instillation is associated with elevated prostate specific antigen (PSA). Materials and Methods: We treated 36 consecutive patients with bladder cancer with a 6-week course of BCG, followed by cystoscopy at 6 weeks. Blood samples for PSA determination were obtained before each BCG instillation and at cystoscopy with each patient also serving as a control. PSA elevation was defined as 2-fold the baseline level in at least 2 specimens and any PSA level greater than 4 ng./ml. was considered clinically significant. Digital rectal examination was done to identify firm nodules and prostate size. The prostate was examined histologically by transrectal ultrasound guided biopsy or after radical cystectomy. Results: We observed elevated PSA in 27 men (75%) during BCG treatment, of whom 15 (41.6%) had a clinically significant elevation. Overall average PSA increased from 1.3 ng./ml. before BCG instillation to 3.8 during treatment (range 0.1 to 21.5, p ⬍0.0001). In those with a clinically significant elevation average PSA increased from 2.31 ng./ml. at baseline to 6.97 during treatment (p ⬍0.0001) and returned to 3.86 ng./ml. 3 months after treatment. Palpation demonstrated prostatic findings in 10 patients, including firm nodules in 7, while there was significantly elevated PSA in 5 with firm nodules and 2 with diffuse prostatic enlargement. Histological examination of the prostate in 10 patients was diagnostic for granulomatous prostatitis, nonspecific inflammation and benign prostatic hyperplasia in 3, 3 and 4, respectively, of whom none had prostate cancer. Conclusions: Intravesical BCG therapy is associated with significantly elevated PSA in up to 40% of cases. This effect is self-limited and PSA reverts to normal in 3 months. Therefore, we suggest that prostate biopsy be withheld in such patients and PSA monitored. KEY WORDS: bladder; prostate-specific antigen; bladder neoplasms; Mycobacterium bovis; administration, intravesical

Since its introduction in 1976, intravesical instillation with bacillus Calmette-Guerin (BCG) has become a valuable treatment for superficial bladder carcinoma. Nevertheless, BCG treatment is frequently associated with side effects, of which the most common are irritative lower urinary tract symptoms. Although granulomatous prostatitis reportedly affects 1.3% of patients after BCG treatment,1 to our knowledge the influence of BCG instillation on serum prostate specific antigen (PSA) has not previously been documented except for the single case report of Bahnson.2 Because of its high predictive value for prostate cancer, elevated PSA is commonly accepted as an indication for prostate biopsy even in the absence of suspicious palpation findings.3 However, considering the prevalence of granulomatous prostatitis in patients who receive intravesical BCG, elevated PSA in this population may be attributable to the inflammatory process rather than to a primary prostatic malignancy. Establishing an association of intravesical BCG treatment with serum PSA elevation would obviate the need for mandatory prostate biopsy, decreasing the risks and adverse effects of prostate biopsy in this patient population. To answer this question we performed a prospective cohort study. MATERIALS AND METHODS

Entered into our study were 38 consecutive men with superficial bladder urothelial carcinoma who were candidates

for intravesical BCG instillation. Indications for BCG treatment included stage T1 urothelial carcinoma, carcinoma in situ and the rapid recurrence of high grade, superficial stage Ta papillary tumors in 14, 3 and 19 cases, respectively. Lesions involved the bladder trigone and neck in 4 cases but not the prostatic urethra in any. Patients previously treated with BCG were not included in our series. Due to the severe side effects of BCG therapy 2 men discontinued the BCG course and withdrew from study. We also excluded from analysis men who were younger than 45 years, had a documented history of prostate cancer, had previously undergone treatment for prostatic carcinoma, received 5␣-reductase inhibitors or required repeat urinary tract manipulation, such as urethral dilation or intermittent catheterization. All patients received a 6-week course of 81 mg. of Connaught strain BCG intravesically, followed by cystoscopy 6 weeks after the final instillation. They were instructed to refrain from voiding during the initial 2 hours after instillation. Intravesical BCG was started a median of 24 days (range 16 to 28) after transurethral bladder cancer resection. Blood samples for PSA determination were obtained before each instillation and before followup cystoscopy. Each patient also served as a control. Serum was separated and maintained at ⫺20C until analysis. Total and free serum PSA was measured using AXSYM* total and free PSA kits,

Accepted for publication June 16, 2000.

* Abbott Laboratories, Abbott Park, Illinois. 1546

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ELEVATED PROSTATE SPECIFIC ANTIGEN AFTER BACILLUS CALMETTE-GUERIN

respectively. Based on a 9% coefficient of variation of PSA analysis we defined elevated PSA as 2-fold the baseline value determined before BCG initiation in at least 2 specimens. Any PSA measurement greater than 4 ng./ml. during BCG therapy was considered clinically significant. Digital rectal examination was performed at visits 1, 3 and 6, and at followup cystoscopy by 3 of us (A. Z., H. C. and D. L.) blinded to previous digital rectal examination findings, who noted prostate size on a scale of 1 to 4 as well as firm nodules. Prostate biopsy was recommended when PSA was persistently elevated to greater than 4 ng./ml. in 2 or more specimens. We used unbalanced repeat measures of analysis of variance to assess continuous variables and Fisher‘s exact test for categorical data. To minimize skewness resulting from relatively high interpatient variability we applied square root correction to all calculations. RESULTS

Of the 38 men who entered the study 2 withdrew due to severe BCG therapy side effects. In a patient with severe dysuria after 2 instillations who refused further BCG therapy PSA increased from a baseline of 3.2 to 5.4 ng./ml. after instillation 2. In the other patient in whom BCG was discontinued due to fever of 38.9C after instillation 3 there was a nonclinical increase in PSA from 2.3 ng./ml. before therapy to a maximum of 3.1 ng./ml. before the final instillation. During therapy we noted an overall statistically significant increase in PSA in 27 cases (75%) from an initial average of 1.3 ng./ml. to a maximal average of 3.81 at BCG instillation 4 (range 0.1 before to 21.5 during treatment, p ⬍0.0001, table 1). PSA was greater than 4 ng./ml. in 15 patients (41.6%), in whom PSA increased from an initial average of 2.31 ng./ml. before to a maximal average of 6.97 during treatment (range

During intravesical BCG instillation serum PSA elevation was statistically significant in all patients compared with baseline. In 15 patients with PSA greater than 4 ng./ml. PSA decreased to normal range 3 months after treatment. Solid line represents average PSA in these patients. Dashed line represents 21 patients in whom elevated PSA did not reach 4 ng./ml. Dotted line represents PSA changes in all 36 patients.

0.5 before to 21.5 during treatment, p ⬍0.0001, see figure). Baseline PSA was greater than 4 ng./ml. in 3 men (4.5, 5.0 and 5.6, respectively), including 2 with significant PSA elevation subsequently and 1 with PSA less than 4 ng./ml. who was not considered to have elevated PSA. PSA decreased to an average of 2.58 ng./ml. 6 weeks after treatment. We noted a slower decrease in the 15 patients with a clinically significant PSA elevation, in whom PSA returned to the normal range 3 months after treatment (average 3.86 ng./ml., see figure). At a cutoff point of 15% there was a low free-to-total PSA ratio in 108 of the 278 blood specimens obtained from all 36

TABLE 1. PSA results Pt. No.

Before Treatment (ng./ml.)

1* 0.7 2* 0.6 3 5.6 4 1.2 5* 1.2 6* 1.6 7 1.2 8 0.5 9* 0.2 10 0.7 11 1.2 12* 0.2 13* 0.4 14 1.3 15* 0.2 16* 0.1 17 1.8 18 0.5 19 2.6 20 0.5 21 1.0 22* 0.3 23* 0.4 24 1.6 25 0.8 26 0.6 27 2.8 28 1.1 29 1.7 30 1.0 31 0.4 32* 0.7 33 4.5 34 2.5 35 1.5 36 5.0 * Elevated PSA. † Clinically significant PSA elevation.

During Treatment (ng./ml.) 1

2

3

4

5

0.9 1.2 8.5† 2.0 0.9 1.3 4.5† 2.5 1.3 1.6 1.1 0.5 0.6 15.5† 0.6 1.9 2.6 10.1† 2.9 0.5 0.9 0.4 0.6 2.2 1.2 0.5 3.0 2.5 2.0 1.8 0.5 0.7 4.6† 7.1† 2.1 3.7

1.5 1.7 15.4† 2.5 1.6 1.4 7.0† 5.4 2.4 0.8 1.0 0.7 0.6 17.5† 1.2 1.0 5.1† 6.0† 4.0 0.6 1.1 0.8 1.0 2.6 1.4 0.6 3.4 21.5† 2.0 2.0 0.4 1.0 6.4† 6.1† 3.3

2.5 2.3 17.2† 3.1 3.1 2.5 7.0† 3.0 2.3 0.8 1.1 0.9 0.9 20.8† 0.8 1.1 5.8† 4.3† 3.9 0.5 2.4 0.8 1.4 6.9† 1.5 0.7 3.2 10.3† 2.2 2.4 0.7 1.3 4.9† 7.8† 1.7 3.2

3.5 2.4 15.2† 3.4

2.8 1.7 18.6† 5.6† 1.4 2.8 7.4† 3.5 1.2 0.8 1.1 0.5 0.7 13.1† 0.6 1.0 5.3† 3.6

3.4 7.4† 3.0 1.8 0.8 1.1 0.4 0.8 15.7† 0.7 1.1 4.9† 4.2† 5.2† 0.6 6.4† 1.0 1.5 10.4† 1.3 0.6 2.7 7.0† 2.0 3.2 0.7 2.3 5.4† 5.2† 1.2

0.5 4.4 1.3 0.8 7.0† 1.5 0.8 3.6 4.1† 2.0 6.5† 0.6 2.0 5.0† 5.5† 1.7 3.2

6 Wks. After Treatment (ng./ml.) 1.3 6.6† 0.9 3.7 3.0 4.6† 0.9 0.7 1.4 0.3 0.6 10.6† 0.9 4.2† 2.8 0.6 3.0 1.3 0.5 5.2† 1.0 0.7 5.6† 2.8 2.0 0.3 1.7

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ELEVATED PROSTATE SPECIFIC ANTIGEN AFTER BACILLUS CALMETTE-GUERIN TABLE 2. PSA results in patient who received 2 BCG courses

Course 6/98 12/98

During Treatment (ng./ml.)

Before Treatment (ng./ml.)

1

2

3

4

5

1.8 2.5

2.6 4.2

5.1 6.5

5.8 5.4

4.9 4.5

5.3 3.7

patients. At a cutoff point of 15% or 20% we observed no association of elevated total PSA greater than 4 ng./ml. with a low free-to-total PSA ratio (p ⫽ 0.74). Compared with pretreatment findings digital rectal examination demonstrated new physical findings in 10 cases during BCG instillation, including diffuse prostatic enlargement in 5 and a firm nodule in 7. Of the 10 patients with new findings 7 also had PSA elevated to greater than 4 ng./ml. Histological examination of the prostate was available in 10 patients, including 4 and 6 who underwent radical cystoprostatectomy and prostate biopsy, respectively. Prostate cancer was not detected in any case. Typical granulomatous prostatitis with caseating necrosis and Langhans’ cells was identified in 3 cases, nonspecific inflammation in 3 and normal prostatic tissue or benign prostatic hyperplasia in 4. Transrectal ultrasound in 7 patients, including 6 who underwent prostate biopsy, revealed a recently suspected firm nodule in 2 with normal PSA, no palpation abnormalities in 1 with elevated PSA and both findings in 4. Hypoechoic lesions were discovered in 6 patients. There was a grossly heterogenic sonographic pattern in 1 man with a firm apical nodule and elevated PSA but no distinct hypoechoic lesion. Fever greater than 38C developed in 7 patients, including 3 and 4 with PSA greater and less than 4 ng./ml., respectively. Fever did not predict clinically significant PSA elevation (p ⫽ 0.99). In addition, there was no correlation of clinically significant, elevated PSA with transitional cell carcinoma recurrence or progression (p ⫽ 0.69). DISCUSSION

Our study demonstrates that intravesical BCG instillation was associated with a significant increase in serum PSA in 42% of cases. PSA elevation is maximal after BCG instillation 3 or 4 and elevated PSA may persist for 3 months after treatment. In 1 patient who underwent a repeat BCG course 6 months after initial treatment PSA typically increased during course 1 but returned almost to the normal range 6 weeks after therapy. PSA was normal before course 2 but subsequently increased during that course (table 2). This biochemical behavior strongly supports an association of BCG instillation with PSA elevation. Considering the inflammatory response generated by BCG therapy and the common finding of granulomatous prostatitis, it is possible that the observed PSA elevation was due to treatment induced prostatitis.4, 5 Although urethral catheterization and rectal examination are associated with possible PSA elevation,6, 7 this association only would not explain the high PSA in some patients, nor persistent PSA elevation up to 3 months after the final BCG instillation. To minimize these potential biases we obtained blood samples before any urinary tract manipulation. While new findings on palpation were less common than increased PSA, digital rectal examination revealed some during the BCG course. Although a firm prostatic nodule is highly predictive of prostatic carcinoma and more specific than PSA,8 in the context of BCG exposure this finding was part of the clinical picture of granulomatous prostatitis. Palpation also demonstrated firm prostatic nodules after BCG therapy in the study of Mukamel et al4 and transrectal prostatic ultrasound revealed typical hypoechoic lesions in the series of Miyashita et al.9 This triad of elevated PSA, firm prostatic nodules and hypoechoic findings on transrectal ul-

6 Wks. After Treatment (ng./ml.) 4.2

trasound that characterizes granulomatous prostatitis indicates that this condition mimics prostate cancer. Nevertheless, our study shows that elevated PSA after BCG treatment is not necessarily diagnostic for coexistent prostate cancer. Since prostate biopsies are invasive, unpleasant and associated with considerable physiological and psychological side effects, our findings may allow a more selective policy for prostate biopsy. We suggest that patients be followed with repeat PSA evaluation for several months and biopsy be reserved for those in whom PSA fails to return to the normal range. According to our experience PSA reverted to the normal range within 3 months after BCG instillation. However, BCG has been reported to persist considerably longer. Bowyer et al documented urine cultures positive for BCG 16 months after treatment in 4% of their patients,10 while Linn et al detected acid-fast bacilli in the prostate and epididymis a year after BCG therapy.11 Therefore, longer followup may be required to ensure that PSA returns to the normal range. Further study is needed to define more accurately the decay curve of PSA after intravesical BCG. Firm prostatic nodules that appear during BCG treatment also need not prompt mandatory biopsy. Rather, serial digital rectal examination may distinguish lesions requiring biopsy that existed before BCG exposure from new onset lesions to which a more conservative policy may be applied. Since PSA is not cancer specific, the free-to-total PSA ratio is often used as an auxiliary factor when determining the indication for prostate biopsy in ambiguous cases. Unfortunately according to our results the free-to-total PSA ratio was inconsistent and, therefore, unreliable.

CONCLUSIONS

Our findings indicate that intravesical BCG therapy was associated with a clinically significant increase in serum PSA in up to 42% of men. This effect is self-limited and PSA returns to the normal level within several months after treatment. Due to the potential adverse effects of prostate biopsy we recommend delaying biopsy for 3 months while monitoring PSA. Eli Fisher provided technical support and advice

REFERENCES

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ELEVATED PROSTATE SPECIFIC ANTIGEN AFTER BACILLUS CALMETTE-GUERIN 7. Batislam, E., Arik, A. I., Karakoc, A. et al: Effects of transurethral indwelling catheter on serum prostate-specific antigen level in benign prostatic hyperplasia. Urology, 49: 50, 1997 8. Cooner, W. H., Mosley, B. R., Rutherford, C. L., Jr. et al: Prostate cancer detection in a clinical urological practice by ultrasonography, digital rectal examination and prostate specific antigen. J Urol, 143: 1146, 1990 9. Miyashita, H., Troncoso, P. and Babaian, R. J.: BCG-induced

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granulomatous prostatitis: a comparative ultrasound and pathologic study. Urology, 39: 364, 1992 10. Bowyer, L., Hall, R. R., Reading, J., et al: The persistence of bacille Calmette-Guerin in the bladder after intravesical treatment for bladder cancer. Br J Urol, 75: 188, 1995 11. Linn, R., Klimberg, I. W. and Wajsman, Z.: Persistent acid-fast bacilli following intravesical bacillus Calmette-Guerin. J Urol, 141: 1197, 1988