Year : 2001 | Volume
: 17 | Issue : 2 | Page : 124--126
B. C. G. plus recombinant interferon α2b in superficial bladder cancer
Gyan Prakash Singh, Usha Singh, US Diwedi, PB Singh
Departments of Urology and Immunology, Institute of Medical Sciences, B.H. U., Varanasi, India
P B Singh
Dept. of Urology, Institute of Medical Sciences, B.H.U., Varanasi - 221 005
We have studied the efficacy of adjuvant therapy in the form of low dose B.C.G. and interferon alpha 2b. In the present study 7patients with superficial bladder carcinoma (6 recurrent and I primary) have been treated by TURBT and intravesical instillation of B. C. G. 80 mg plus interferon alpha 2b 10 million units weekly for 8 weeks. All patients accepted the therapy without significant morbidity and complication. Follow-up,period ranges between 11-16 months and none of the patients have developed recurrence till date.
Interferon alpha 2b along with B.C.G. is a good alternative agent, for prophylaxis in case of high grade and recurrent bladder tumour
|How to cite this article:|
Singh GP, Singh U, Diwedi U S, Singh P B. B. C. G. plus recombinant interferon α2b in superficial bladder cancer
.Indian J Urol 2001;17:124-126
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Singh GP, Singh U, Diwedi U S, Singh P B. B. C. G. plus recombinant interferon α2b in superficial bladder cancer
. Indian J Urol [serial online] 2001 [cited 2023 Feb 8 ];17:124-126
Available from: https://www.indianjurol.com/text.asp?2001/17/2/124/21041
The vast majority of bladder tumours are transitional cell carcinoma with a major ( > 70% ) percentage of these tumours being superficial that is limited to mucosa and lamina propria. Transurethral resection remains the first line of therapy for superficial bladder tumours. Majority of these superficial bladder tumours develop recurrence following transurethral resection.  Factors that lead to increased rate of recurrence and progression following TURBT are high grade, high stage, multifocality and presence of dysplasia or carcinoma in situ. Following transurethral resection adjuvant therapy in the form of intravesical chemotherapy or intravesical immunotherapy (B. C. G.) are often used to prevent or delay recurrence and progression. The role of intravesical B. C. G. as a mode of adjuvant therapy for prevention or delay of recurrence and progression of superficial TCC of bladder has been established.
Large number of studies undertaken have shown that using B. C. G. for prophylaxis the recurrence rate is 17-20% within 5 years. ,, This has proved B. C. G. as an agent superior to intervesical chemotherapy. Despite high efficacy dose-limiting toxicity associated with intravesical B.C.G. therapy include dysuria (91 %) frequency (90%), haematuria (46%) with B.C.G. cystitis and B.C.G. sepsis requiring ATT (6%). 
Given the substantial number of patients who experience recurrence and progression and toxicity with intravesical B.C.G. new less toxic and more efficient approaches are necessary.
Immunotherapeutic agents like interferon α2b, Bropirimine have been investigated as agents for prophylaxis against recurrence and progression. A number of progressive clinical trials have been undertaken using interferon α2b as a single agent. Conclusion drawn from these studies is that intravesical interferon α2b is still inferior to B.C.G. when used as a single agent, but effective in substantial number of patients who are refractory to B.C.G. With a dose variation from 10-100 million units weekly, the most frequent side effect is mild to moderate flu-like symptom. In vitro studies with human cell lines have demonstrated that combination of interferon α2b and B.C.G. is more effective in inhibiting proliferation of TCC cells than either agent alone. , B.C.G. and interferon α2b are bio-compatible and can be instilled intravesically as a single mixture. 
We have studied the efficacy, tolerability and toxicity of combination therapy of low dose B.C.G. and interferon α2b as an agent for prophylaxis.
Material and Methods
Patients with superficial bladder tumours both primary and recurrent have been included in study. Tumour diagnosis was established based on history, clinical examination, urine cytology, cystoscopy and biopsy. Tumour staging was done by USG, CT scan and histopathological examination of the TUR specimen. 2 weeks following TURBT patients were subjected to adjuvant intravesical immunotherapy with intravesical instillation of 80 mg B.C.G and 10 million units of interferon α2b suspended in 50 ml of normal saline for 2 hrs weekly for 8 weeks. Patients with Ta Gr I lesion were not subjected to adjuvant therapy.
All patients were followed up with urine cytology and cystoscopy every month for first 3 months, every 3 months for l year and every 6 months thereafter.
The response to treatment was evaluated by referring to duration of disease-free survival, number of recurrence, time to recurrence and progression of disease.
The study started in May 1998. Total number of patients included in the study is 7. All the 7 patients were male. Age ranged between 45 to 70 yrs. All the 7 patients were having tumours that were solitary, papillary with size between 1-3 cm (Mean 1.8 cm) without any presence of carcinoma in situ. 6 of the tumours were recurrent tumour. 4 of them were T Gr II lesions. 2 of them had undergone TURBT followed by intravesical B.C.G. 120 mg weekly for 6 weeks and other 2 had undergone only TURBT for primary tumour. 2 of the tumours were T, Gr III and had undergone TURBT followed by intravesical. B.C.G. 120 mg weekly for 6 weeks. Mean time to recurrence following TURBT plus intravesical B.C.G. was 14 months. Mean time to recurrence following TURBT was 9 months [Table 1]. The status of the primary tumour in these cases is not known as they were treated for primary tumour elsewhere. 1 was primary tumour with Ta Grade III lesion.
All patients completed the 8-week schedule of B.C.G. 80 mg and interferon α2b 10 million international units. Minor symptom like mild haematuria developed in 6 of total 56 instillations. Haematuria was not associated with symptoms like dysuria, frequency, fever. None of the patients developed flu-like symptom.
The response to treatment is evaluated by referring to the duration of disease-free survival, the number of recurrence and progression of disease. All the 7 patients are in follow-up [Table 1]. The follow-up period ranges from 11 to 16 months (mean follow-up 13months). No patient has developed recurrence till now.
Superficial bladder tumours are prone to develop recurrence and progression following simple transurethral resection only, particularly in presence of risk factors like high grade, high stage, multifocality, carcinoma in situ, etc. Adjuvant therapy in the form of intravesical instillation of chemotherapeutic agents like Mitomycine, thiotepa, doxorubicin and immunotherapeutic agents like B.C.G. are in practice. Intravesical chemotherapeutic agents have failed to provide significant long-term reduction in recurrence and progression and are associated with toxicity. Several clinical trials have demonstrated the superior efficacy of B.C.G. However with intravesical B.C.G. recurrence rate of 17-20% is not insignificant. Toxicity associated with the standard dose of B.C.G. (120 mg weekly for 6 weeks) like dysuria, frequency haematuria and occasionally cystitis and sepsis requiring antitubercular therapy have forced patients to abandon the therapy.
The role of recombinant interferon α2b in the treatment of superficial TCC of bladder is still under investigation. The interferon exhibits direct and indirect anti-tumour effects. In-vitro interferon α2b demonstrates direct anti-proliferative activity on bladder cancer cells grown in culture.  The indirect anti-tumour effects of interferon are likely mediated via stimulation of potent cellular immune response, by enhancing activation of cytotoxic T lymphocyte, LAK cell activity. ,
The efficacy of intravesical recombinant interferon α2b in preventing recurrence and progression has been evaluated in several studies. ,, Recurrence rate ranges from 21 to 60 %. These studies demonstrated interferon as an agent inferior to B.C.G. in prevention and delay of recurrence.
In-vitro studies with murine and human cell lines demonstrated that combination of recombinant interferon α2b and B.C.G. inhibit proliferation of bladder cancer cells more effectively than either agent alone. , B.C.G. and recombinant interferon α2b are biocompatible so they can be instilled intravesically as a single mixture. 
This will provide either equal or enhanced therapeutic effects compared with B.C.G. alone while allowing reduction of the dose of B.C.G. Such a strategy can lead to reduction in B.C.G.-related toxicity and morbidity without affecting the therapeutic effect.
Stricker et al  used intravesical B.C.G. 60 mg with escalating dose of recombinant interferon α2b 10-100 million international units in 12 patients with superficial TCC (7 cases with carcinoma in situ and 5 cases with papillary T 1 Gr II lesions). The result showed response rate of 86% in carcinoma in situ, 60% in papillary tumour in a median follow-up period of 12 months.
Bercovich et al in a study reported improved tolerance with B.C.G. plus interferon α2b compared to B.C.G. alone. When used for prophylaxis with a median follow-up of 17 months recurrence rate was 22% in B.C.G plus interferon group.
In our study which includes 7 patients subjected to B. C. G. 80 mg and interferon α2b 10 million units weekly for 8 weeks tolerance has been very good. Only 6 out of 56 instillations were followed by mild haematuria. Over a mean follow-up period of 13 months the recurrence has been nil.
The total number of cases is not large. Randomized trial could not be possible because majority of our patients could not afford the cost of the drug which is around Rs. 30,000. Only 7 patients could afford it and have been included in present study.
We conclude that by combining reduced dose of BCG with recombinant interferon α2b it may be possible to make the treatment more tolerable for the patients without compromising efficacy. Although our result is encouraging a large multi-institutional randomized trial is recommended. However, the high cost may be a constraint to a large randomized trial.
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