|Year : 2000 | Volume
| Issue : 2 | Page : 129-133
Intravesical BCG+interferon-α-2b in prevention of recurrence in transitional cell carcinoma of urinary bladder
Nayan K Mohanty, MN Mandal, AN Sinha, Alok K Jha
Departments of Urology and General Surgery, Safdafjang Hospital, New Delhi, India
Nayan K Mohanty
D-II/87. West Kidwai Nagar New Delhi - 110 023
| Abstract|| |
Bladder malignancy is the 11th most common cancer in the world with more than 2,00,000 new cases diagnosed every year 90% of these are TCC, of which 75-80% are superficial in nature.
Our aim in this study was to find the efficacy, safety and cost effectiveness of a low dose intravesical imnumotherapy with BCG (70 mg) + Interferon-α-2b in prevention of its recurrence and prolonging disease progression interval.
Between Jan. '94 to Dec. '98, 100 patients with superficial TCC (Ta, TI) of urinary bladder with or without Tis after transurethral resection of tumor underwent intravesical instillation of BCG (70 ing) + Interferon-α-2b (5million IU) weekly for 8 weeks, fortnightly for 8 weeks, monthly . for 8 weeks . followed by maintenance dose at the end of 9th, 12th, 18th & 24th months with follow-up for 60 months.
Results: At the end of 60 months of follow-up 36 patients (36%) showed complete response, 44 patients (44%) showed partial response, resulting in a total response rate of 80% while 20% progressed to higher stage & grade. Patients' tolerance was good and adverse reaction was low 19%.
Conclusion: This study has shown that a low dose combined therapy with BCG and Interferon is not only safe, well tolerated, cost effective but also highly efficient in preventing recurrences in 36%, maintaining superficial nature of the disease in another 44% with a disease progression free interval of 5 years in 80% of cases.
Keywords: Immunotherapy; BCG; Interferon; Combined low Dose
|How to cite this article:|
Mohanty NK, Mandal M N, Sinha A N, Jha AK. Intravesical BCG+interferon-α-2b in prevention of recurrence in transitional cell carcinoma of urinary bladder. Indian J Urol 2000;16:129-33
|How to cite this URL:|
Mohanty NK, Mandal M N, Sinha A N, Jha AK. Intravesical BCG+interferon-α-2b in prevention of recurrence in transitional cell carcinoma of urinary bladder. Indian J Urol [serial online] 2000 [cited 2013 May 22];16:129-33. Available from: http://www.indianjurol.com/text.asp?2000/16/2/129/22212
| Introduction|| |
Bladder cancer is the 11th most common malignancy in the world with more than 200,000 new cases diagnosed every year. In U.S.A. it is the 2nd most common urological malignancy. About 90% of bladder carcinomas are transitional cell type of which 75-80% are superficial in nature at the time of their first presentation. Recurrences of these superficial tumors occur within 6 months following transurethral resection of tumors (TURT) with approximately 20% of them progressing to higher grade in that period. Many intravesical instillations of drugs have been carried out for the past one and a half decades to prevent recurrences and prolong disease progression free interval. Though transurethral resection of these tumors remains the first line of therapy, intravesical therapy to prevent its recurrence is necessary.
The role of immuno modulators has recently been accepted as the latest adjuvant therapy for preventing recurrences. BCG has been tried as a single immuno modulator since 1979 with good results but with higher rate of toxicity, while Interferon-α-2b though less efficient as compared to BCG in term of preventing tumor recurrences has an advantage of being less toxic, as a 2nd line of therapy after BCG recurrence, but is costly.
Since the mode of action of BCG and that of Interferon are different and in BCG recurrence cases, Interferon has shown good response and vice versa, it was thought that by combining low dose of BCG with Interferon one can achieve less toxicity, and also it would be more economical with better efficacy in preventing recurrences and delay disease progression free interval in these malignancies.
BCG is a biological response modifier; when given intravesically it produces a complex local immune reaction by producing local inflammation leading to secretion of multiple cytokins including interleukin (IL-2, IL-12), Interferon, tumor necrosis factor with an increased CD4/CD8 T cell ratio.
Previous work has shown that BCG produces a complete response rate of 55-60% but toxicity in the form of dysuria, frequency, haematuria, cystitis, spesis is 30-35%. On the other hand the role of Interferon-a-2b has been observed specially to augment the immuno modulatory effect of BCG by amplifying the production of cytokins such as IL-2, IL- 12, Interferon gamma, apart from having direct inhibitory effect on the proliferation of tumor bladder cancer cells. Intravesical Interferon-α-2b increases the cytotoxic activity of T-lymphocytes, natural killer cells (NKC) by increasing infiltration of these cells into bladder wall. Furthermore recent studies suggest that combination of these two drugs in a lower dose have shown better response rate than with either agent alone. With the above facts in mind we undertook a study of a low dose combined intravesical immunotherapy using 70 mng of BCG with 5 million IU of Interferon-α-2b (Intron-A Fulford Scherring) to achieve low toxicity. better efficacy in the form of longer tumor free recurrence rate and prolonged disease progression free interval keeping in view the cost factor.
| Materials and Methods|| |
Between Jan. '94 and June '99, a total number of 121 patients diagnosed as superficial TCC of urinary bladder (Ta,T1) with or without associated Cis were included in this study. All these patients after a detailed history and clinical examination had routine haematological, liver function test (LFT) and renal function studies, before being subjected to transabdominal ultrasonography, urine for cytology for malignant cells, bladder tumor antigen stat (BTA), CT scan of abdomen and X-ray chest for an accurate clinical staging followed by cystopanendoscopy (CPE) with biopsy as an outpatient procedure under local anaesthesia (LA) was done in all cases, not only to reach a histopathological diagnosis but also to know the number, size and appearance of the tumor mass.
Once the diagnosis and clinical staging was established as Ta & TI transitional cell carcinoma (TCC) of urinary bladder, they were subjected to transurethral resection of tumor (TURT) under spinal anaesthesia/general anaesthesia (SA/GA). All resections were done by the author only to have an uniformity. Meticulous care was taken to completely resect the tumor mass alongwith base, so as to give enough tissue for histopathological study.
Within one week of resection, the histopathology report confirming the superficial nature of the tumor, these patients were subjected to intravesical instillation of 5 million IU of Interferon-α-2b (Intron-A, Fulford Scherring) diluted with 30 ml of physiological normal saline in combination with 70 mg of BCG mixed in 30 ml of normal saline, under all aseptic measures, through a 8F red rubber catheter after evacuating the residual urine, as a day care procedure weekly for 8 weeks, fortnightly for 8 weeks, monthly for 8 weeks, at the end of 9th, 12th, 18th and 24th months following resection as maintenance dose - a total of 18 instillations in 2 years. Each instillation was for 2 hours duration during which the patient was asked to lie for half hour in prone, supine, left lateral and right lateral position so as to allow the drug to reach each quadrant of the bladder.
- Fresh haemogram estimation was done at the beginning of each instillation.
- During follow-up periodic check cystoscopies were carried out during the therapy at the end of 3rd, 6th, 9th, 12th months during the first year, 6 monthly for next 2 years and yearly thereafter.
- In event of any recurrence the patients were subjected to transurethral resection of tumor and if histopathology proved it to be still low stage and low grade, the patients were continued in the same schedule, i.e., for Tis, Ta, T1 stage.
- In case histopathology showed progression of the disease to higher stage i.e., T2, T3, T4 the patients were excluded from the study.
| Response Criteria|| |
Our result was evaluated as complete response, partial response or no response.
Complete response was defined as normal appearance at cystoscopy with or without biopsy with no tumor recurrence. Recurrence of TCC of similar or lesser grade & stage were designated as partial response while progression to higher grade and stage was termed as no response. Toxicity was evaluated through patient's report, observation by the investigators and local systemic reaction.
| Observation|| |
Out of a total number of 121 patients, there were 21 dropouts/dead leaving a total of 100 patients for evaluation of this therapy.
- All these patients were followed up for an average period of 60 months ranging from 48-70 months.
- 80 patients were male and 20 female making the sex ratio as M : F 4 : 1. Maximum incidence in female was in the 5th decade, a decade earlier than their male counterparts (T. 1).
- The age of our patients ranged from 48-83 years, mean age being 63.56 years. T. I shows the age & sex distribution of our patients, the majority of them belonged to 5th & 6th decade of life (72%) the maximum being in the sixth decade (40%).
All the 100 patients under study had at least one episode of haematuria which was the commonest symptom.
Associated symptoms were of increased frequency of micturition, anaemia, fever, weakness (T. 2).
- Out of the total 100 patients 36 were of stage Ta, 5 patients were of stage T1 and 8 had Tis with TI (T.3).
- Histopathology revealed 52 patients of G-II, 44 patients G-III and 4 patients G-IV (T. IV). The higher the number, the higher was the grade without any statistical significance.
- History revealed 60% were former tobacco smokers, 24% smokers of tobacco, while 16% were non-smokers, thereby revealing tobacco smoking is a significant co-factor in developing bladder cancer.[Table 1],[Table 2],[Table 3],[Table 4]
| Result|| |
The response to treatment was evaluated by referring to the duration of disease free survival, the number of recurrences and time interval and progression of the disease [Table 5].
Complete response rate which was 84% at the end of 1 st year dropped down to 36% at the end of 60 months follow-up while partial response at the end of 12 months follow-up rose to 44% at the end of 60 months, while during the first year none of the patients progressed to higher grade/stage, but subsequent progression to higher stage was observed resulting in 20% at the end of 60 months follow-up.
| Side Effects|| |
The total incidence of side effects was 19%, the most common being dysuria with UTI, followed by urgency and frequency. Minor side effects like headache, itching, myalgia and general weakness was also observed and one patient had hepatitis in whom the drug was withdrawn temporarily.
| Discussion|| |
The primary aim of this clinical trial was to establish the safety and efficacy of the low dose combination therapy of BCG + Interferon-α-2b therapy at a low cost, so as to achieve a longer period of tumor free recurrence rate and prolonged disease progression free interval in patients with confirmed bladder malignancy.
- Morales et al  - in 1976 first used BCG in management of superficial TCC with an optimal dose of 120mg of BCG, the toxicity was high. In order to reduce toxicity and simultaneously increase the efficacy, a second immunomodulator in the form of Interferon-α-2b is currently used with introduction of maintenance dose by many workers (Morales el  ).
- Catalona et a1  used high dose of Interferon as a monotherapy to achieve good result but it was costly. Similarly Glashan et a1  and Distasi  using high dose of Interferon achieved good results.
Stricker P et al  have shown that the additive antiproliferative effect of BCG + Interferon-α-2b on cell line derived from human bladder cancer cells. A combination of BCG+Interferon-α-2b at simulated clinical concentration had a similar anti-proliferative effect to a double dose of BCG alone .
- BCG and Interferon-α-2b have a direct anti-proliferative effect on bladder tumor cells. In addition, these cells which were unresponsive to BCG previously, became susceptible to combined anti-tumor activities of BCG plus Interferon. Our observation augmented the clinical trials with combination of BCG & Interferona-2b in the hope to reduce BCG associated toxicity.
There is considerable evidence to suggest that Interferon-α-2b + BCG both at low dose has better efficacy in the treatment of superficial TCC.
We achieved a good overall result, 60 months of recurrence free interval in 36% and disease progression free interval in 80% of our patients in the study. Our study shows similar results as to that shown by Bercovich et al,  O'Donnell,  Engelmann. 
One of our aims was to reduce toxic effect of the therapy; with low dose of both the drugs from 16% this reduction was well perceived as only 19% of our patients had the adverse effect as compared to 40% by Lamn et al. 
Finally by reducing the dose of both the drugs, the cost of the therapy was reasonably low.
- Our study has achieved a complete tumor free recurrence rate of 36% at the end of 5 years follow-up with another 44% having superficial tumor recurrences, thereby giving a 80% disease progression free interval on 5 years follow-up.
| Conclusions|| |
In conclusion our study has shown that a low dose combination immunotherapy of BCG + Interferon-a-2b is not only safe, economical but also very effective in achieving a longer tumor free recurrence rate and a prolonged disease progression free interval with very little adverse effect, but to achieve this maintenance dose at a periodic interval after initial therapy seems to be mandatory.
| References|| |
|1.||Morales A, Eidinger D, Bruce AW. Intracavitary bacillus Calmette - Guerin in the treatment of superficial bladder tumors. J Urol 1976; 116: 180-183. [PUBMED] |
|2.||Morales A, Nickel JC, Wilson JWL. Dose response of Bacillus Calmette-Guerin in the treatment of superficial bladder cancer. J Urol 1992; 147: 1256-1258. |
|3.||Catalona WJ, Hudson MA, Gillen DP, Andriole GL, Ratliff TL. Risk, and benefits of repeated course, of intravesical bacillus Calmette-Guerin therapy for superficial bladder cancer. J Urol 1987: 137: 220-224. |
|4.||Glashan RW. A randomised controlled study of intravesical a-2b Interferon in carcinoma-in-situ of the bladder. J Urol 1990; 144: 658-661. [PUBMED] |
|5.||Distasi SM et al. Intralesionai alpha Interferon in papillary superficial TCC of the bladder - A pilot study. Br J Urol 1992; 422-426. |
|6.||Stricker P, Pryor K, Nicholson T et al. Bacillus Calmette-Guerin + Intravesical Interferon-a-2b in patient with superficial bladder cancer. Urol 1996; 48: 957-962. |
|7.||Bercovich et al. BCG vs BCG+Interferon-a-2b recombinate net tumor superficial della vesica. Arch Ital Urol 1995; 67: 257-260. |
|8.||O'Donnell HA. Experimental and clinical evidence of enhancement of BCG efficacy by adding Interferon- a-2b. J Urol 1997; 157: 382. |
|9.||Engelmann U et al. Interferon-a-2b instillation prophylaxis in superficial bladder cancer - a prospective controlled three armed trial. Anti Cancer drugs (Suppl 3) 1992; 33. |
|10.||Lamn DL et al. Long term results of intravesical therapy for superficial bladder cancer. Urol Clin North Am 1992; 19: 573-580. |
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]