bropirimine and Carcinoma-in-Situ

Bacillus Calmette-Guerin (BCG) has been shown to be the most effective agent for the treatment of superficial bladder cancer since its approval by the US Food and Drug Administration for the treatment of carcinoma in situ of the bladder in 1990. Recently, augmentation of BCG immunotherapy with interferon-alpha2b and other agents is emerging as salvage therapy for those patients who fail initial treatment. This review summarizes the role of various immunotherapeutic agents in the treatment of bladder cancer, with special emphasis on the appropriate administration and schedule of BCG therapy as well as salvage with the combination of BCG with interferon-alpha2b.

Topics: Adjuvants, Immunologic; Antineoplastic Agents; BCG Vaccine; Carcinoma in Situ; Cytosine; Drug Administration Schedule; Garlic; Humans; Interferon alpha-2; Interferon-alpha; Interleukins; Plant Extracts; Prognosis; Recombinant Proteins; Salvage Therapy; Urinary Bladder Neoplasms; Vitamins

To explore new treatment strategies in high-risk superficial bladder cancer patients, such as recurrent carcinoma in situ (CIS) or pT1 transitional cell carcinoma after intravesical bacillus Calmette-Guérin (BCG).. Mechanism of action, pharmacology and the results of clinical phase I and II trials with the oral biological response modifier bropirimine are reviewed.. In a phase II trial in which CIS patients were treated, 17 complete responses were seen in 29 patients (59%) at the 3,000-mg dose level. Moreover, this trial indicated that bropirimine is a promising alternative in BCG recurrent or BCG intolerant patients: in 13 BCG failures, 6 complete responses were seen. Side effects are mild to moderate, mainly flu-like symptoms.. These results suggest that bropirimine is effective at 3,000 mg/day, and that patients with prior BCG therapy may be salvaged by bropirimine treatment.

Topics: Adjuvants, Immunologic; Antineoplastic Agents; Carcinoma in Situ; Clinical Trials as Topic; Cytosine; Dose-Response Relationship, Drug; Humans; Neoplasm Recurrence, Local; Urinary Bladder Neoplasms

Bropirimine has been shown to have activity against carcinoma in situ (CIS) of the bladder in a previous phase-I trial. A review of three completed clinical trials as well as ongoing studies is presented to provide a current update.. Details of the initial phase-I trial are reviewed, as are findings of a subsequent phase-II trial in bladder CIS and a multicenter study in upper tract CIS. All have used a dose of 3 g/day for 3 consecutive days each week, repeated weekly for up to 1 year. Cytology must be positive prior to treatment, and both biopsies and cytology must be negative after therapy for the patient to be considered a complete response.. In the phase-II trial in bladder CIS, 20 (61%) of 33 patients had a complete response. Responders included patients with prior bacillus Calmette-Guérin (BCG) therapy, uni- and multifocal CIS, and primary and secondary CIS. Responses were seen in 10 (48%) of 21 evaluable patients with upper tract CIS. Toxicities in both studies were manageable in most patients. Trials underway include bropirimine in BCG-failed CIS, a randomized comparison to BCG in previously untreated patients, and a trial of the two together.. Bropirimine does have activity against both bladder and upper tract CIS on the dose schedule used to date.

Topics: Adjuvants, Immunologic; Antineoplastic Agents; Carcinoma in Situ; Clinical Trials as Topic; Cytosine; Humans; Immunotherapy; Neoplasm Recurrence, Local; Ureteral Neoplasms; Urinary Bladder Neoplasms

This European phase III clinical trial was part of an intercontinental study which was closed prematurely by the sponsor. The study was designed to compare the effects of oral bropirimine with intravesical BCG, the current standard treatment in patients with newly diagnosed bladder carcinoma in situ (CIS).. A total of 55 BCG-naive patients with bladder CIS were randomized to receive bropirimine (n = 27) or BCG (n = 28). Bropirimine was orally administered at a dose of 3 g/day for 3 consecutive days with a 4-day drug-free interval for up to 1 year. BCG-Tice instillations were administered weekly for 2 x 6 weeks. Both biopsies and cytology had to be negative for the patient to be considered a complete responder (CR).. The percentage of dropouts for all of the adverse events was 4% for bropirimine and 14% for BCG. The most frequently reported local events in the bropirimine- versus the BCG-treated group were irritative complaints, 64 vs. 89% (p = 0.03) and hematuria, 24 vs. 61% (p < 0.01). The most frequently reported systemic events in the bropirimine- versus the BCG-treated group were fever 4 vs. 21%, flu syndrome 24 vs. 7%, headache 28 vs. 11% and nausea 24 vs. 11% (all p > 0.05). A total of 92% of the patients treated with bropirimine had a CR with a mean duration of 12.6 months (95% CI 9.2-15.9). In the BCG group, all of the patients had a CR with a mean of 12.3 months (95% CI 8.5-16.0).. This study shows that bropirimine, an orally administered drug that can be self-administered to outpatients with more acceptable local toxicity compared to BCG, could be an effective first-line therapy in patients with CIS of the urinary bladder. Continued investigation of bropirimine is warranted to increase its clinical utility.

Topics: Adjuvants, Immunologic; Administration, Oral; BCG Vaccine; Carcinoma in Situ; Chi-Square Distribution; Cytosine; Female; Humans; Male; Survival Rate; Treatment Outcome; Urinary Bladder Neoplasms

A follow-up investigation was conducted on a Late Phase II clinical study of bropirimine for carcinoma in situ (CIS) of the bladder. We previously reported that 48 patients were enrolled and 17 patients achieved complete remission (CR) in the Late Phase II study. Of the 17 CR patients, 5 had recurrence, but 9 were recurrence free for a year and 5 have remained so for more than 2 years (median follow-up: 29.1 +/- 4.2 months). The 1-year and 2-year recurrence-free rates calculated using the Kaplan-Meier method were 70.3% and 61.5% respectively. Of all the 47 bropirimine-treated patients, 11 underwent total cystectomy (median follow-up: 31.8 +/- 5.2 months). The rates of bladder preservation after 1 year, 2 years, and 3 years calculated using the Kaplan-Meier method were 87.2%, 80.7%, and 74.0% respectively. Of the 39 patients who did not respond to bropirimine or suffered from recurrence after bropirimine treatment, 19 received subsequent intravesical bacillus Calmette-Guerin (BCG) therapy and 13 achieved CR (68.4%). This suggests that bropirimine does not decrease the efficacy of BCG therapy. In the present study, the prognosis was confirmed to be favorable after bropirimine therapy. Bropirimine would thus seem to be a useful oral anticancer agent for bladder CIS.

Topics: Administration, Intravesical; Administration, Oral; Antineoplastic Agents; BCG Vaccine; Carcinoma in Situ; Cytosine; Drug Administration Schedule; Follow-Up Studies; Humans; Urinary Bladder Neoplasms

Bropirimine is an oral immunomodulator that has demonstrated anticancer activity in transitional cell carcinoma in situ (CIS) in both the bladder and upper urinary tract. Activity also has been documented in patients after prior therapy with bacille Calmette-Guérin (BCG). To more accurately estimate bropirimine's efficacy in BCG-resistant bladder CIS, a Phase II trial was performed. A separate analysis was performed in additional patients intolerant of BCG toxicity.. Patients received bropirimine 3.0 g/day by mouth for 3 consecutive days, weekly, for up to 1 year. Bladder biopsies and cytologic examination were performed quarterly. Complete response (CR) required negative biopsy and cytology results.. Twenty-one of 86 patients entered were not evaluable. CR was seen in 21 (32%; 95th percentile confidence interval [CI], 21% to 44%) of 65 evaluable patients, including 14 (30%, CI 17% to 43%) of 47 BCG-resistant, and 7 (39%, CI 16% to 61%) of 18 BCG-intolerant patients. Overall, by intent-to-treat analysis, CR was thus seen in 21 (24%) of 86 subjects. Most BCG-resistant patients were failures to BCG without relapse, and had received 12 to 36 (median 12) BCG treatments; intolerant patients had received 4 to 11 treatments (median 6). Response duration ranged from 65 to 810 days, with median not yet reached (but greater than 12 months). Thirteen (15%) of 86 stopped bropirimine due to toxicity. Progression to invasive or metastatic disease during or immediately after therapy was documented in only 4 patients (6%), all nonresponders.. Bropirimine may be an alternative to cystectomy for some patients with bladder CIS who have failed or have not tolerated BCG. Further evaluation to improve responses and durability is warranted.

Topics: Adjuvants, Immunologic; Administration, Oral; BCG Vaccine; Carcinoma in Situ; Cytosine; Humans; Remission Induction; Treatment Failure; Urinary Bladder Neoplasms

Late Phase II clinical study with bropirimine (U-54461S), a novel oral antitumor agent that has interferon inducing and anti-proliferative activities, was conducted in patients with bladder CIS at 38 institutions nationwide. To investigate the efficacy and safety of the treatment, bropirimine was administered to the patients at the dose of 750 mg every two hours, three times a day, for three consecutive days with four-day drug withdrawal, based on the results of the preceding clinical studies up to early phase II. Among the 48 patients registered, 41 patients were evaluable for antitumor efficacy. Complete response (CR) was observed in 17 of them, no change (NC) in 18 patients, and progressive disease (PD) in 6 patients; so the efficacy rate was 41.5%. Classified by patient background, the efficacy rates were 58.3% (7/12) in patients with primary bladder CIS, 34.5% (10/29) in those with secondary bladder CIS, 45.5% (10/22) in those with Grade 3, and 23.8% (5/21) in those previously given chemotherapeutic agents or BCG by intravesical or other routes. Adverse drug reactions frequently observed were influenza-like symptoms such as fever and generalized malaise and gastrointestinal symptoms like anorexia and nausea/vomiting; these symptoms were all Grade 2 or milder. Abnormalities in laboratory tests, such as an elevation in GOT/GPT, neutropenia, and leukopenia were observed. These adverse effects were all tolerated by the patients. From the above results, bropirimine was considered to be a useful oral agent for the treatment of bladder CIS.

Topics: Administration, Oral; Anorexia; Antineoplastic Agents; Carcinoma in Situ; Cytosine; Drug Administration Schedule; Fever; Humans; Interferon Inducers; Nausea; Urinary Bladder Neoplasms; Vomiting

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.. Patients were treated with bropirimine 3.0 g/day by mouth for 3 consecutive days each week up to 1 year. Cystoscopy with biopsies and bladder wash cytology were performed quarterly.. 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-Guérin (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 15 months, all Stage Ta or T1. Mild toxicity (grade I or II) suggestive to 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 1 tachycardia/palpitations or chest pain each were noted in 5%.. 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 front-line therapy because of its ease of administration.

Topics: Adjuvants, Immunologic; Administration, Oral; Adult; Aged; Aged, 80 and over; Carcinoma in Situ; Cytosine; Female; Humans; Male; Middle Aged; Urinary Bladder Neoplasms

Bropirimine has been shown to be effective in treating approximately 50% of patients with carcinoma in situ (CIS) of the bladder in recent clinical trials. Patients with upper tract CIS were treated with bropirimine to determine whether this oral drug might be effective in that setting.. Twenty-four patients with negative radiographic findings and positive cytologic evidence for upper tract CIS in one or both ureters received bropirimine (3.0 g/day orally) for 3 consecutive days each week for up to 1 year. Ureteral collection of urine or barbotage for cytologic analysis was performed quarterly thereafter.. Ten (48%) of 21 evaluable patients had a negative ureteral cytologic analysis after 12 weeks (5 patients) or 24 weeks (5 patients). Of these 10 patients, 8 continue to have negative cytology for a period of 3 to 30 months (median, more than 9 months). In 2 patients, negative cytology reverted to positive at 6 and 9 months, respectively, during therapy. Twelve (50%) of the 24 patients reported no toxicity. Three patients stopped treatment at 2, 3, and 3 weeks due to pruritic rash, nausea and vomiting, and severe bone pain, respectively. Therapy was stopped in 1 additional patient between 4 and 5 months because of transient liver enzyme elevations, yet this patient has had a continuous negative cytologic analysis for more than 9 months.. Orally administered bropirimine may be effective therapy for CIS of the ureter or renal pelvis, with acceptable toxicity in most patients. Further efforts to better define this activity as well as the possible need for maintenance or intermittent long-term therapy are warranted.

Topics: Adjuvants, Immunologic; Aged; Aged, 80 and over; Carcinoma in Situ; Cytosine; Female; Humans; Male; Middle Aged; Ureteral Neoplasms

Topics: Antineoplastic Agents; BCG Vaccine; Carcinoma in Situ; Cytosine; Humans; Urinary Bladder Neoplasms

A total of 34 patients with measurable superficial transitional cell cancer of the bladder entered into a phase 1, nonrandomized, noncomparative trial to assess the toxicity of the oral interferon inducer bropirimine. Of the patients 26 were also evaluable for response. The toxicity of bropirimine was minimal. At the 3-month evaluation 6 patients had experienced complete regression of tumor and had negative cytology studies, and 2 had partial responses. The majority of complete responses were in patients with carcinoma in situ only, with most responses seen at higher dose levels. One patient with papillary tumor and carcinoma in situ had a complete response. Some early responses appear to be durable. Most importantly, a high rate of complete response was noted at higher dose levels among patients who had failed prior therapy with bacillus Calmette-Guerin. Further clinical trials of bropirimine in bladder cancer appear warranted.

Topics: Administration, Oral; Antineoplastic Agents; Carcinoma in Situ; Carcinoma, Papillary; Carcinoma, Transitional Cell; Cytosine; Drug Evaluation; Humans; Urinary Bladder Neoplasms