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ORIGINAL ARTICLE
Year : 2000  |  Volume : 16  |  Issue : 2  |  Page : 129-133
 

Intravesical BCG+interferon-α-2b in prevention of recurrence in transitional cell carcinoma of urinary bladder


Departments of Urology and General Surgery, Safdafjang Hospital, New Delhi, India

Correspondence Address:
Nayan K Mohanty
D-II/87. West Kidwai Nagar New Delhi - 110 023
India
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Source of Support: None, Conflict of Interest: None


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   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 2019 Oct 21];16:129-33. Available from: http://www.indianjurol.com/text.asp?2000/16/2/129/22212



   Introduction Top


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 Top


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 Top


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 Top


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 Top


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 Top


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 Top


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 [2] - 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 [1] ).
  • Catalona et a1 [3] used high dose of Interferon as a monotherapy to achieve good result but it was costly. Similarly Glashan et a1 [4] and Distasi [5] using high dose of Interferon achieved good results.


Stricker P et al [6] 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, [7] O'Donnell, [8] Engelmann. [9]

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. [10]

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 Top


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 Top

1.Morales A, Eidinger D, Bruce AW. Intracavitary bacillus Calmette - Guerin in the treatment of superficial bladder tumors. J Urol 1976; 116: 180-183.  Back to cited text no. 1  [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.  Back to cited text no. 2    
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.  Back to cited text no. 3    
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.  Back to cited text no. 4  [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.  Back to cited text no. 5    
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.  Back to cited text no. 6    
7.Bercovich et al. BCG vs BCG+Interferon-a-2b recombinate net tumor superficial della vesica. Arch Ital Urol 1995; 67: 257-260.  Back to cited text no. 7    
8.O'Donnell HA. Experimental and clinical evidence of enhancement of BCG efficacy by adding Interferon- a-2b. J Urol 1997; 157: 382.  Back to cited text no. 8    
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.  Back to cited text no. 9    
10.Lamn DL et al. Long term results of intravesical therapy for super­ficial bladder cancer. Urol Clin North Am 1992; 19: 573-580.  Back to cited text no. 10    



 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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    Abstract
    Introduction
    Materials and Me...
    Response Criteria
    Observation
    Result
    Side Effects
    Discussion
    Conclusions
    References
    Article Tables

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