Donald L. Lamm

MAINTENANCE BACILLUS CALMETTE-GUERIN IMMUNOTHERAPY FOR RECURRENT TA, T1 AND CARCINOMA IN SITU TRANSITIONAL CELL CARCINOMA OF THE BLADDER: A RANDOMIZED SOUTHWEST ONCOLOGY GROUP STUDY

PURPOSE Bacillus Calmette-Guerin (BCG) immunotherapy has been widely accepted as the optimal treatment for carcinoma in situ and high grade superficial transitional cell carcinoma. However, controversy remains regarding the role of maintenance therapy, and its long-term effect on recurrence and progression. MATERIALS AND METHODS All patients in the study had transitional cell carcinoma of the bladder with carcinoma in situ or an increased risk of recurrence. The criteria for increased risk were 2 or more episodes of tumor within the most recent year, or 3 or more tumors within 6 months. At least 1 week following biopsy of carcinoma in situ and resection of any stage Ta or T1 transitional cell tumors 660 patients were started on a 6-week induction course of intravesical and percutaneous Connaught BCG. Three months following initiation of BCG induction therapy 550 consenting patients were stratified by purified protein derivative skin test and the presence of carcinoma in situ, and then randomized by central computer to receive BCG maintenance therapy (maintenance arm) or no BCG maintenance therapy (no maintenance arm). Maintenance therapy consisted of intravesical and percutaneous BCG each week for 3 weeks given 3, 6, 12, 18, 24, 30 and 36 months from initiation of induction therapy. The 384 eligible patients who were disease-free at randomization constitute the primary intent to treat analytic group because they could be followed for disease recurrence. All patients were followed for adverse effects of treatment, recurrence, disease worsening and survival. RESULTS No toxicities above grade 3 were noted in the 243 maintenance arm patients. The policy of withholding maintenance BCG from patients with increased side effects may have diminished the opportunity to observe severe toxicity. Estimated median recurrence-free survival was 35.7 months (95% confidence interval 25.1 to 56.8) in the no maintenance and 76.8 months (64.3 to 93.2) in the maintenance arm (log rank p<0.0001). Estimated median time for worsening-free survival, defined as no evidence of progression including pathological stage T2 disease or greater, or the use of cystectomy, systemic chemotherapy or radiation therapy, was 111.5 months in the no maintenance and not estimable in the maintenance arm (log rank p = 0.04). Overall 5-year survival was 78% in the no maintenance compared to 83% in the maintenance arm. CONCLUSIONS Compared to standard induction therapy maintenance BCG immunotherapy was beneficial in patients with carcinoma in situ and select patients with Ta, T1 bladder cancer. Median recurrence-free survival time was twice as long in the 3-week maintenance arm compared to the no maintenance arm, and patients had significantly longer worsening-free survival.

Incidence and Treatment of Complications of Bacillus Calmette-Guerin Intravesical Therapy in Superficial Bladder Cancer

Intravesical therapy with bacillus Calmette-Guerin (BCG) has proved to be more effective in the prophylaxis and treatment of superficial bladder tumors and carcinoma in situ than most chemotherapeutic agents. Compared to intravesical chemotherapy, instillations with BCG provoke more local and systemic reactions. In addition to the commonly induced granulomatous inflammatory changes in the bladder, which produce irritative symptoms, this therapy may cause systemic side effects varying from mild malaise and fever to, in rare instances, life-threatening or fatal sepsis. We report the incidence and varieties of toxicities in 2,602 patients treated with intravesical BCG. Side effects are classified according to local and systemic toxicity. Treatment options vary according to the severity of toxicity from delaying or withholding instillations to treatment with antituberculous drugs for up to 6 months. In general, 95% of the patients have no serious side effects. Recognition of risk factors, particularly traumatic catheterization or concurrent cystitis, that result in systemic BCG absorption, as well as the prompt and appropriate treatment of early side effects should significantly decrease the incidence of severe toxicity.

A randomized trial of intravesical doxorubicin and immunotherapy with bacille Calmette-Guérin for transitional-cell carcinoma of the bladder

BACKGROUND In carcinoma of the bladder, both intravesical chemotherapy and immunotherapy can induce tumor regression and reduce the rate of recurrence, but the relative merits of these two therapies are unclear. We conducted a multi-institutional study to address this question. METHODS Patients with rapidly recurrent (stage Ta and T1) or in situ transitional-cell carcinoma of the bladder were randomly assigned to receive either doxorubicin administered intravesically or bacille Calmette-Guérin (BCG) administered both intravesically and percutaneously. The 262 eligible patients were followed for a median of 65 months. Complete responses to treatment of carcinoma in situ were confirmed by biopsy and cytologic analysis of the urine. RESULTS For patients with Ta and T1 tumors without carcinoma in situ, the estimated probability of being disease free at five years was 17 percent after doxorubicin, as compared with 37 percent after immunotherapy with BCG (P = 0.015). The median times to treatment failure (termination of treatment, due to persistence, recurrence, or progression of disease) were 10.4 and 22.5 months, respectively. For patients with carcinoma in situ the complete-response probability estimates (i.e., the estimated probability of documented disappearance of disease) were 34 percent for doxorubicin (23 of 67 patients) and 70 percent for BCG (45 of 64 patients) (P less than 0.001); the median times to treatment failure were 5.1 and 39 months, respectively. The probability of being disease-free at five years survival among the patients with carcinoma in situ was 18 percent after treatment with doxorubicin and 45 percent after BCG therapy. Patients treated with BCG had a higher incidence of toxic systemic effects and a larger number of local irritative symptoms than patients treated with doxorubicin, but few of these adverse reactions were severe. CONCLUSIONS As compared with intravesical doxorubicin, immunotherapy with BCG provides improved protection against the recurrence of superficial bladder cancer.

Complications of Bacillus Calmette-Guerin Immunotherapy in 1,278 Patients with Bladder Cancer

Our series of 195 patients, plus 134 reported on in the literature and 949 reviewed by various physicians provide 1,278 patients for review of bacillus Calmette-Guerin therapy complications. Cystitis occurred in 91 per cent of the patients. Complications identified included fever more than 103F in 50 patients (3.9 per cent), granulomatous prostatitis in 17 (1.3 per cent), bacillus Calmette-Guerin pneumonitis or hepatitis in 12 (0.9 per cent), arthritis or arthralgia in 6 (0.5 per cent), hematuria requiring catheterization or transfusion in 6 (0.5 per cent), skin rash in 5 (0.4 per cent), skin abscess in 5 (0.4 per cent), ureteral obstruction in 4 (0.3 per cent), epididymo-orchitis in 2 (0.2 per cent), bladder contracture in 2 (0.2 per cent), hypotension in 1 (0.1 per cent) and cytopenia in 1 (0.1 per cent). Most of the severe irritative side effects and subsequent systemic complications can be prevented with prophylactic isoniazid given for 3 days, beginning the morning of treatment. Patients with life-threatening systemic bacillus Calmette-Guerin infection or anaphylaxis should receive 500 mg. cycloserine twice daily for 3 days in addition to combination antituberculous therapy because the rapid action of this drug may be life-saving. Direct intralesional bacillus Calmette-Guerin immunotherapy can produce sepsis and death, and should be avoided but intravesical bacillus Calmette-Guerin generally is well tolerated and has produced no complication in more than 95 per cent of the patients treated.

Use of a New Tumor Marker, Urinary NMP22, in the Detection of Occult or Rapidly Recurring Transitional Cell Carcinoma of the Urinary Tract Following Surgical Treatment

PURPOSE We evaluated the ability of an immunoassay for nuclear matrix protein 22 (NMP22 test kit) to predict the subsequent disease status of patients with transitional cell carcinoma of the urinary tract at approximately 10 days after transurethral resection of bladder tumor. MATERIALS AND METHODS A total of 90 patients with transitional cell carcinoma provided voided urine samples at least 5 days postoperatively. NMP22 was determined using a commercial test kit. At initial cystoscopic examination 3 to 6 months later the disease status was recorded, and the NMP22 values before and after transurethral resection of bladder tumor were compared. RESULTS Of 125 followup cystoscopic examinations (60 patients had 1, 26 had 2, 3 had 3 and 1 had 4 recurrences) transitional cell carcinoma was pathologically confirmed in 33. No malignancy was present at 79 examinations (if tumor was seen endoscopically, pathological evaluation indicated atypia, dysplasia or no abnormality). NMP22 values in these 2 populations were significantly different (malignancy median 20.81 units per ml. and no malignancy median 5.72 units per ml., Mann-Whitney U test for differences between 2 medians p = 0.00005). Of the 33 recurrences 23 (70%) had NMP22 values greater than the reference range (10 units per ml.). Additionally, NMP22 identified all 6 subjects (100%) who had invasive disease 3 to 6 months later. Of 72 patients with NMP22 less than 10 units per ml. 62 (86%) had no malignancy at subsequent cystoscopy. CONCLUSIONS NMP22 was highly predictive of tumor status at followup cystoscopy. This quantitative, noninvasive assay, with high negative predictive value (86%) and sensitivity to detect malignancy (100% for invasive disease and 70% overall), may be a helpful adjunct to cytology and endoscopy for monitoring disease status after endoscopic tumor resection.

Bacillus Calmette-Guerin Immunotherapy for Bladder Cancer

Bacillus Calmette-Guerin immunotherapy has been found by a number of investigators to be effective in the treatment and prevention of superficial bladder cancer. While the optimal protocol for bacillus Calmette-Guerin remains to be determined, experience with 92 randomized and 30 nonrandomized (high risk) patients followed for up to 5 years provides information that may improve future protocols. Side effects of bacillus Calmette-Guerin are observed to increase with increasing frequency and duration of treatment. The protection from tumor recurrence has persisted: only 6 of 30 patients (20 per cent) treated with bacillus Calmette-Guerin have had recurrent tumor compared to 14 of 27 controls (52 per cent, p equals 0.008, chi-square test), and mean time to recurrence increased from 24 to 48 months (p less than 0.005, Savage). Skin test reactivity to purified protein derivative is particularly useful in predicting response to bacillus Calmette-Guerin immunotherapy. Currently, 60 patients have been randomized to receive bacillus Calmette-Guerin immunotherapy and only 1 of 22 patients (4.5 per cent) in whom the purified protein derivative skin test results converted from negative to positive has had recurrent tumor, compared to 12 recurrences (32 per cent) in patients whose skin tests were positive before treatment or failed to convert following treatment (p equals 0.014, chi-square). Seven recurrences (33 per cent) developed in 21 patients whose skin tests remained negative (p equals 0.015) and 5 recurrences (29 per cent) developed in 17 patients whose tests previously were positive (p equals 0.068, Fishers test, not significant). The benefit of percutaneous bacillus Calmette-Guerin is suggested by the observations that the recurrence rate in patients treated with intravesical bacillus Calmette-Guerin alone is 40 per cent, and all 7 patients whose purified protein derivative skin tests were negative continued to have negative results when percutaneous bacillus Calmette-Guerin was omitted (p equals 0.003). Among high risk patients a marked decrease in or complete prevention of recurrent tumor was observed in 82 per cent of 22 patients treated previously with chemotherapy and 11 of 14 (78 per cent) with carcinoma in situ have had a complete response.

Bacillus Calmette-Guerin immunotherapy of superficial bladder cancer.

Thirty-seven patients were enrolled in a randomized prospective study to compare standard surgical therapy for superficial bladder cancer to standard therapy plus bacillus Calmette-Guerin (BCG). Side effects of BCG have been tolerated well and include dysuria in 95 per cent of the patients, urinary frequency in 83 per cent, hematuria in 39 per cent, fever in 22 per cent and nausea in 22 per cent. Of 19 control patients 8 (42 per cent) had recurrent tumors in the followup period, compared to 3 of 18 patients (17 per cent) treated with BCG. One patient treated wih BCG had 2 recurrences, yielding a recurrence rate of 22 per cent in the group receiving BCG compared to 42 per cent in controls. When the incidence of recurrent tumors in matched intervals before and after entry into the protocol is compared, no change in the rate of tumor recurrence (p equals 0.726 chi-square) occurred in controls, whereas tumor recurrences were reduced significantly in the group treated with BCG (p equals 0.010 chi-square). The reduction in tumor recurrence in patients treated with BCG compared to controls is statistically significant (p equals 0.029 chi-square). Of 4 patients who presented with new bladder tumors remain free of tumor after BCG therapy, while 2 of 5 comparable control patients developed recurrent tumors. Intravesical and percutaneous BCG immunotherapy appears to decrease the rate of tumor recurrence in patients followed for 1 year.

A Review of Current Guidelines and Best Practice Recommendations for the Management of Nonmuscle Invasive Bladder Cancer by the International Bladder Cancer Group

PURPOSE Although the European Association of Urology, First International Consultation on Bladder Tumors, National Comprehensive Cancer Network and American Urological Association guidelines all provide an excellent evidence-based framework for the management of nonmuscle invasive bladder cancer, these guidelines vary with respect to important issues such as risk level definitions and management strategies for these risk categories. Therefore, we built on the existing framework provided by current guidelines, and provide consensus on the definitions of low, intermediate and high risk nonmuscle invasive bladder cancer, as well as practical recommendations for the treatment of patients in each of these risk categories. MATERIALS AND METHODS An international committee of experts on bladder cancer management identified and analyzed the European Association of Urology, First International Consultation on Bladder Tumors, National Comprehensive Cancer Network and American Urological Association guidelines as well as the published English language literature related to the treatment and management of nonmuscle invasive bladder cancer available as of April 2010. RESULTS Based on review of the current guidelines and literature, the International Bladder Cancer Group developed practical recommendations for the management of nonmuscle invasive bladder cancer. CONCLUSIONS Complete transurethral bladder tumor resection is recommended for all patients with nonmuscle invasive bladder cancer. For low risk disease a single, immediate chemotherapeutic instillation after transurethral bladder tumor resection is recommended. For intermediate or high risk disease there is no significant benefit from an immediate, postoperative chemotherapeutic instillation. For intermediate risk disease intravesical bacillus Calmette-Guérin with maintenance or intravesical chemotherapy is recommended. For high risk disease bacillus Calmette-Guérin induction plus maintenance is recommended. The appropriate management of recurrence depends on the patient level of risk as well as previous treatment, while the management of treatment failure depends on the type of failure as well as the level of risk for recurrence and disease progression.

Apparent Failure of Current Intravesical Chemotherapy Prophylaxis to Influence the Long-Term Course of Superficial Transitional Cell Carcinoma of the Bladder

During the 4 decades since the first introduction of intravesical chemotherapy, 3,899 patients were enrolled in 22 randomized prospective controlled studies. Of these 22 studies 13 reported a statistically significant benefit of intravesical chemotherapy. With varying followup, the reported decrease in the incidence of patients with tumor recurrence averaged only 14% (range -3 to +43%). Unfortunately, long-term (5-year) studies show no decrease in the incidence of recurrent tumor. Maintenance chemotherapy has failed to improve these results and data suggest that a single early postoperative instillation may, in fact, be most effective. Among 10 studies that include progression data none showed decreased tumor progression, and overall among 2,011 randomized patients progression occurred in 7.5% of those receiving intravesical chemotherapy and 6.9% of those treated by surgery alone. Since intravesical chemotherapy has been demonstrated in animal models to be carcinogenic, these data raise the concern that intravesical chemotherapy might possibly be carcinogenic in humans. In the absence of demonstrated long-term benefit we question the advisability of routine prophylactic intravesical chemotherapy.

Improved Detection of Recurrent Bladder Cancer Using the Bard BTA stat Test

OBJECTIVES To evaluate the BTA stat Test in the detection of recurrent bladder cancer. METHODS Sensitivity and specificity were determined using frozen voided urine samples from patients with recurrent bladder cancer, volunteers, patients with nonurologic conditions, and patients with a history of bladder cancer but free of disease. Results of cytology and the original BTA Test were compared with the sensitivity of the BTA stat Test in a large subgroup of the patients with cancer. RESULTS The BTA stat Test detected 147 (67%) of 220 recurrent cancers. For those urine samples with previous cytologic and BTA Test results available, cytology had a sensitivity of 23%, the BTA Test 44%, and the BTA stat Test 58% for detection of recurrent cancer (P < 0.001, stat versus cytology). The specificity of the BTA stat Test was 72% for benign genitourinary disease and 95% in healthy volunteers. CONCLUSIONS The BTA stat Test has high sensitivity and is significantly superior to voided urine cytologic analysis in the detection of recurrent bladder cancer.