Indian Journal of Urology
ORIGINAL ARTICLE
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

Correspondence Address:
P B Singh
Dept. of Urology, Institute of Medical Sciences, B.H.U., Varanasi - 221 005
India

Abstract

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


How to cite this URL:
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


Full Text

 Introduction



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. [10] 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. [2],[9],[11] 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%). [7]

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. [12],[14] B.C.G. and interferon α2b are bio-compatible and can be instilled intravesically as a single mixture. [17]

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.

 Results



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.

 Discussion



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. [4] 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. [1],[18]

The efficacy of intravesical recombinant interferon α2b in preventing recurrence and progression has been evalu­ated in several studies. [5],[13],[15] 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. [12],[14] B.C.G. and recombinant interferon α2b are biocompatible so they can be instilled intravesically as a single mixture. [17]

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 [16] 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[3] 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.

 Conclusion



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.

References

1Jackson AM, Hawkyard SJ, Prescott S et al. An investigation of factors influencing the in vitro induction of LAK activity against a variety of human bladder cancer cell lines. J Urol 1992; 147: 207-­211.
2Brossman SA. Experience with BCG in patients with superficial bladder carcinoma. J Urol 1982; 128: 27-30.
3Berovich E et al. BCG vs BCG plus recombinant interferon a2b in superficial bladder tumour. Arch Ital Urol Androl 1995; 67: 257.
4Borden EC, Grovenman DS, Nasut, et al. Antiproliferative activi­ties of interferons against human bladder carcinoma cell lines in vitro. J Urol 1984: 132: 800-803.
5Kostacopoules A et al. Intravesical interferon a2b administration in the treatment of superficial bladder tumours. Euro Urol 1984; 18: 201.
6Lamm DL, Thor DE. Harris SC et al. BCG immunotherapy of su­perficial bladder cancer. J Urol 1980; 124: 38-42.
7Lamm DL, Stogdill VD, Stogdill BJ, Crispen RG. Complications of BCG immunotherapy in 1278 patients with bladder cancer. J Urol 1986; 135: 272-274.
8Lamm DL, Dehaven JI, Shriver J et al. A randomized prospective comparison of oral versus intravesical and percutaneous BCG for superficial bladder cancer. J Urol 1990; 144: 65-67.
9Lamm DL, Crawford ED et al. Randomized intergroup comparison of intravesical Mitomycin and BCG prophylaxis in superficial TCC of the bladder. Urol Oncol 1995; 1: 119.
10Malmstrom, Norlen BL Recurrence, progression and survival in bladder cancer. A retrospective analysis of 232 patients with more than 5yrs follow-up. Scand J Urol Nephrol 1987; 21: 185.
11Morales A, Eidinger D. Bruce AW. Intracavitary BCG in the treat­ment of superficial bladder tumors . J Urol 1976: 116: 180-183.
12Okamoto E, Kinne RKH, Sokeland J. Interferon, modify in-vitro proliferation of human bladder TCC in the presence of Doxorubicin and Mitomycin C. J Urol 1996; 156: 1492-1495.
13Portillo J, Martin B et al. Results of months' follow-up of a double blind, randomized, prospective clinical trial using intravesical in­terferon a2b in the prophylaxis of stage T, TCC of bladder. Urol­ogy 1997; 49: 187.
14Pryor K, Stricker P et al. Antiproliferative effects of BCG and in­terferon α2b on human bladder cell lines in vitro. Cancer Immunol Immunother 1995: 41: 309.
15Bartoletti R, Rizzo M et al. Interferon a2b in superficial bladder cancer: prophylaxis. toleration and long-term follow-up. Anti Can­cer Res 1991; 11: 2167.
16Stricker P, Pryor K. BCG plus interferon a2b in patients with su­perficial TCC of bladder. Urology 1996; 48: 957.
17Downs TM, Szilvasi A, O'Donnell MA. Pharmacological bio-com­patibility between intravesical preparations of BCG and interferon a2b. J Urol 1997; 158: 2311-2315.
18Tzai TS, Lin SN. Interferon alb can alter the lytic susceptibility of murine bladder transitional cell carcinoma (MBT-2) by their origi­nal poor specific cytotoxic tumour infiltrating lymphocytes. J Urol 1992; 147: 523-527.