|Year : 2001 | Volume
| Issue : 2 | Page : 127-131
Ten years' experience with adjuvant intravesical immunotherapy in management of superficial transitional cell carcinoma of urinary bladder - a review
NK Mohanty, Alok K Jha, S Saxena, Sujit Kumar, RP Arora
Department of Urology and Institute of Pathology, Safdarjang Hospital, New Delhi, India
N K Mohanty
D-II/87, West Kidwai Nagar, New Delhi - 110 023
Source of Support: None, Conflict of Interest: None
| Abstract|| |
The incidence of Transitional Cell Carcinoma (TCC) of urinary bladder is increasing worldwide. Patients with superficial TCC of urinary bladder can have a survival period of 10 years if they are detected at an early stage and appropriate intravesical adjuvant immunotherapy is instilled in time.
A total number of 440 patients of superficial TCC were instilled intravesically BCG & Interferon a-2b as single drug or in combination and followed up.
BCG though was most efficient, had high toxic rate while Interferon α-2b was expensive, whereas a low dose combination therapy of both showed excellent result in reducing tumor recurrences & prolonging disease progression free interval.
The author reviews his experience of 10 years in management of these malignancies with intravesical immunotherapy and concludes that a low dose BCG (60mg) with Interferon α-2b (5 million IU) has shown to be very effective in reducing tumor recurrences, prolonging disease-progression-free interval with a very low toxicity in such patients. To achieve this a periodic maintenance dose therapy is absolutely necessary.
Keywords: Intravesical; Immunotherapy; Superficial Transtitional Cell Carcinoma
|How to cite this article:|
Mohanty N K, Jha AK, Saxena S, Kumar S, Arora R P. Ten years' experience with adjuvant intravesical immunotherapy in management of superficial transitional cell carcinoma of urinary bladder - a review. Indian J Urol 2001;17:127-31
|How to cite this URL:|
Mohanty N K, Jha AK, Saxena S, Kumar S, Arora R P. Ten years' experience with adjuvant intravesical immunotherapy in management of superficial transitional cell carcinoma of urinary bladder - a review. Indian J Urol [serial online] 2001 [cited 2019 Nov 15];17:127-31. Available from: http://www.indianjurol.com/text.asp?2001/17/2/127/21042
| Introduction|| |
According to the 1990 estimate of the American Cancer Society, urinary bladder malignancy accounted for 7% of all new cancer cases in men and 3% among women  and it was the ninth leading cause of death in man and fourteenth among women as well as being the fifth most common malignancy among men and ninth most common malignancy among women. Approximately 57,000 new cases were diagnosed annually by end of 1990.
In the last decade this scenario has changed drastically. At the end of 1999, it is now the fourth most common malignancy among males and eighth most common malignancy among females. It is the eleventh most common malignancy worldwide. It accounted for 11.5% of all new cancer cases among men and 5% among women. Around 200,000 new cases are diagnosed worldwide annually by end of 1999. These statistics clearly show the increasing trend in its incidence, thanks to rapid global industrialization, urbanization and free use of tobacco.
The prognosis and survival period of these malignancy entirely depends on the stage and grade of the diseases at the time of detection. A 5-year survival rate of 85% among superficial tumors drops to 43%, when it becomes muscle invasive and 9% when there is distant metastasis.
Approximately 75-85% of these tumors are superficial in nature at the time of onset (Herr),  one-third being pTl and two-third being pTa and about 75% of these tumors recur after initial TURT because they are notorious for their polychromotropic properties which make necessary constant surveillance of these patients to detect early recurrences. The earlier the recurrence, worse the prognosis. Hence the primary aim in management of these tumors is not only to detect them early and resect them but also to prevent their recurrences and progression to higher stage and grade, so that a longer tumor-recurrence-free and disease-progressionfree period is achieved.
Based upon the hypothesis that bladder cancer is a systemic disease of the uroepithelium, the concept of adjuvant intravesical therapy has been designed in order to reduce its recurrence rate and prolong disease-progression-free interval.
For the last three decades different chemotherapeutic and immunomodulators have been in use to treat such recurrences. Intravesical immunotherapy is based on the fact that placing an immune stimulant in contact with superficial TCC will stimulate a host response in tumors.
Though the exact mechanism of BCG action is not clear it is presumed that BCG provokes an immediate inflammatory response in which macrophages are activated. A delayed reaction in which macrophages ingest BCG and additionally stimulate BCG sensitised T-cells to produce lymphokinines which results in a further cascade of activation of parts of the immune system. 
On the other hand Interferon has demonstrated anti-proliferative, surface membrane, antiviral and immunomodulatory activities in vivo.  Ever since Interferon α-2b was first described in 1957 by Isaac and Lindermann  for its antiviral properties, the focus has shifted to its antiproliferative, immunomodulatory and oncogene-regulation properties.
In our present study we review our result of the use of immunomodulators like BCG and Interferon α-2b in management of superficial TCC of urinary bladder in the last 10 years.
| Materials and Methods|| |
Between July '89 to Dec. '99 all superficial TCC of urinary bladder treated in our department after initial TURT, were subjected to adjuvant intravesical immunotherapy using either BCG (Danish 1331), Interferon α-2b (Intron-A) alone or in combination and followed up regularly with urine cytology, ultrasonography, cystoscopy and lately by BTA stat.
A total number of 440 new patients were enrolled in our study during this period which was done phase-wise.
Between the period July '89 to July '92, a total number of 165 patients having pTa & pT1 disease after one week of TURT were subjected to intravesical instillation of 120 mg of BCG (Danish 1331) weekly for 2 hours' duration for 6 consecutive weeks with an average follow-up for 30 months. Results observed were analysed.
The availability of Interferon α-2b (Intron-A) in our country in early 1992 showed a new pathway in its use for management of these tumors.
Between July '92 to July '94, a pilot study was conducted, using low dose Interferon α2b (Intron-A) particularly on BCG refractory/resistant cases. A total number of forty-five patients of superficial TCC were subjected to intravesical instillation of 9 million IU of Intron-A weekly for 2 hours' duration for consecutive 8 weeks with an average follow-up of 24 months. Results were then analysed, paper published. 
From our above two studies, a few relevant factors were observed:
- That BCG had a better efficacy in reducing tumor recurrences and disease progression free interval as compared to Interferon α2b.
- That toxicity of BCG at a dose of 120 mg weekly was very high.
- The toxicity of Interferon α-2b was very low and in significant in nature.
- The efficacy of Interferon is dose related.
- The cost of Interferon is very high as compared to BCG.
- A maintenance dose at periodic interval is mandatory to achieve a high rate of tumor-recurrence-free period and a longer disease-progression-free interval.
- And BCG and Interferon are biocompatible, hence can be used in combination.
With the above facts in mind we undertook another study between July '94 to July '99 using a low dose of BCG (60 mg) in combination of low dose of Interferon (5 million IU) so as to achieve low toxicity, better efficacy while keeping in view to reduce the cost factor.
During this period a total number of 230 patients of pTl & pTa stage were subjected to intravesical instillation of the above combination therapy mixed with 50ml of physiological saline after I week of TURT weekly for 8 weeks, fortnightly for the 8 weeks, monthly for 8 weeks followed by maintenance dose at the end of 9 th , 12 th , 18 th & 24 th month. A total number of 18 instillations over a period of 2 years. Each instillation was of 2 hours' duration with an average follow-up period of 60 months ranging from 48-70 months. Then the paper was published. 
| Results|| |
A total number of 165 patients underwent the therapy of which 105 patients were of pTa and 60 patients of pTl . 40 patients had grade I, 85 patients were grade II and 40 patients grade III tumors. Result showed a reduction in tumor recurrences in 72% of patients at the end of first year follow-up but subsequently fell to 30% at the end of 30 months' follow-up. The greatest drawback of the study was the high incidence of toxicity 33% (55 patients) with 4 deaths due to hepatitis and BCG sepsis [Table - 1].
Morales in 1976 was the first to use BCG in management of superficial TCC.  The optimal treatment regime of BCG was still not determined then. Morales recommended a single course of 6-weeks' therapy while Zlotta et al  confirmed later that a 6-weeks' single course was unable to induce sustained symptom response and reactivation of lympho-proliferative response was observed when a second BCG course was administered. This maintenance schedule has now been propagated by Lamm & co-workers." Our result showed a high recurrence rate on subsequent follow-ups may be explained due to the fact that we did not recommend the maintenance dose therapy in our initial study as it was not clear then, whether a maintenance therapy was required or not. The high toxic rate of 33% in our series may be due to the use of 120 mg of BCG. Though BCG has a high efficacy rate in reducing tumor recurrences, but a maintenance dose at periodic intervals is mandatory to reduce the subsequent recurrences.
Interferon α2b (Monotherapy)
Our result of this pilot study done between July '92 to July '94 was very encouraging. A total number of 45 patients with 28 patients having pTa and 17 patients having pT1. 18 patients were grade I, 20 patients were grade II and 7 patients had grade III tumors. Results showed a mean recurrence-free-period of 24 months in 55% (25 patients), 20% (9 patients) showing superficial recurrences, and 25% (11 patients) progressing into muscle invasive stage. Drug compliance was excellent with a very low toxicity rate in the form of flu-like symptoms in 5 patients (11 %). A recurrence-free-interval of 24 months was achieved in 55% with another 25% having superficial recurrence, thereby giving a disease-progression-free interval in 75% of patients of 24-months' follow-up.
The advantage of this therapy was not only a very low adverse reaction rate with insignificant symptoms but also achieving tumor recurrence free in BCG refractory or resistant cases clearly indicating that Interferon is the drug of choice in BCG resistant cases. Interferon was first used by Torti in 1988.  A better reduction in tumor recurrences rate in our study could have been achieved if a higher dose schedule used as efficiency of Interferon is directly proportional to its dose. Our constraint in using high dose Interferon was its high cost.
Low dose BCG+Interferon (Combined)
A total number of 230 patients, 130 patients of pTa and 100 patients of pTl between July '94 to July '99 were enrolled in the study. 90 patients had Gr. I, 100 patients had Gr. II and 40 patients had Gr. III tumors. At the end of 1st year follow-up 84% had no tumor recurrences which dropped to 36% at the end of 5 th year of follow-up, while 16% had superficial tumor recurrences at the end of first year follow-up which rose to 44% at the end of 5 th year of follow-up. [Table - 2] None of these patients had a disease progression to higher grade at the end of 1 st year of follow-up. The incidence of adverse reactions at the end of follow-up was found to be 19%, most common being dysuria and UTI with no mortality. In 2 patients drug was withdrawn temporarily for transient hepatitis, who completed the course later on. In this study of ours, we have achieved a very low toxicity rate as compared to BCG alone, reduced the cost of the therapy to half of that of Interferon alone and achieved a very high disease-progression-free interval of 5 years in 80% of our patients.
| Discussion|| |
The primary aim in management of superficial TCC of urinary bladder is its early detection and institution of appropriate intravesical adjuvant therapy to reduce tumor recurrences so as to have a prolonged disease-progression-free interval after initial TURT.
The use of chemotherapeutic agents, which was tried earlier has now been replaced by immunomodulators because chemotherapeutic drugs act only when the tumors are actually present or actively multiplying. Maintenance dose cannot be given because of their high toxicity and there is no evidence to claim that it can reduce diseaseprogression rate though it has shown to reduce tumor recurrences on short-term studies.
Out of the many immunomodulators available, the commonly used are BCG, Interferon and Interleukin-2.
The author in his 10 years of experience had the opportunity of using both BCG and Interferon alone and lately their combination in low dose and has achieved a good result in management of these malignancy with the following observations:
a) BCG is the best available immunomodulator in reducing tumor recurrence rate and giving longer disease-progression-free period in superficial TCC of urinary bladder.
b) Interferon α-2b is the second line of therapy particularly in BCG resistant/refractory cases.
c) The toxicity of BCG can be reduced using low dose of BCG (60 mg) in combination with low dose of Interferon (5 million IU) which is not only economical but also can achieve a high rate in reduction of tumor recurrences and give a 5-year-disease-progression-free interval in 80% of patients.
Stricker P et al,  have shown similar results. A combination of two immunomodulators at stimulated clinical concentration had a similar antiproliferative effect to a double dose of BCG.
BCG+Interferon have a direct antiproliferative effect on bladder tumor cells. In addition, these cells which were unresponsive to BCG previously become susceptible to combined antitumor activities of BCG+Interferon. Our observations augmented the clinical trial with the combination therapy with the hope not only to reduce BCG associated toxicity but also to achieve a high efficacy rate.
To achieve this a maintenance dose therapy at periodic intervals after initial booster therapy seems to be mandatory.
We achieved a good overall result of 60 months of recurrence-free interval in 36% with another 44% having superficial recurrences thereby giving a 5-year disease-progression-free interval in 80% of our patients. Our results are similar to that shown by Bercovich et al,  O'Donnell  and Engelmann. 
| Conclusion|| |
With the above experience the author concludes that a low-dose combined intravesical immunotherapy with BCG and Interferon α-2b gives an excellent result in reducing tumor recurrences, prolonging disease-progression-free interval with low toxicity in the management of superficial TCC of urinary bladder. But to achieve this a maintenance dose therapy at periodic intervals seems to be mandatory.
| Acknowledgement|| |
We are grateful to Mr. Mahendra Joshi of the Dept. of Urology, who has helped in typing the manuscript and getting the printouts.
| References|| |
|1.||American Cancer Society - Cancer facts & figures 1990. |
|2.||Herr HW, Landone VP. Intravesical therapy for superficial bladder cancer. AUA update series 1989; 8: (Lesson) 12. |
|3.||Heney NM, Proppe K, Prout GR et al. Invasive bladder cancer: Tumour configuration, lymphatic invasion and survival. J Urol 1983; 130:895-897. |
|4.||Jong WH de. Steerenbery PA et al. BCG and its use for cancer immunity - Tumor immunology mechanics, diagnosis, therapy. Amsterdam 1987. |
|5.||Torti FM, Lum BL. Superficial bladder cancer - risk of recurrences & potential role for interferon therapy. Cancer 1987; 59:613. |
|6.||Issac A, Lindermann J. Virus interference, the interferon. Proc R Soc Lond B Biol Sci 1957; 147: 258-267. |
|7.||Mohanty NK, Gulati P. Saxena S. Role of Interferon a-2b in prevention of superficial TCC recurrences. Urol Int 1997; 59:194-196. |
|8.||Mohanty NK, Mandal MN, Sinha AN et al. Intravesical BCG + Interferon a-2b in prevention of recurrences in TCC of urinary bladder. Indian J Urol 2000: 16: 128-133. |
|9.||Morales A, Eidinger D et al. Intracavity BCG in treatment of superficial bladder tumors. J Urol 1976; 116: 180-183. |
|10.||Zlotta R, Drowart A et al. The need of a maintenance BCG therapy is suggested by the inability of intravesical BCG to promote a longterm systemic immune T cell activation. J Urol 1997; 157: (Abstract) 383. |
|11.||Lamm DL. Long-term results of intravesical therapy for superficial bladder cancer. Urol Clin North Am 1992; 19: 573-580. |
|12.||Torti FM, Shortliffe LD, William RD et al. Alpha interferon in superficial bladder cancer - a northern California Oncology group study. J Clin Oncol 1988; 6 : 476. |
|13.||Stricker P, Pryor K, Nicholson T et al. Bacillus calmette guerin & intravesical interferon a-2b in patients with superficial bladder cancer. Urol 1996; 48: 957-962. |
|14.||Bercovich et al. BCG vs BCG+Interferon a-2b recombinate net tumor superficial della vesica. Arch Ital Urol Androl 1995; 67: 257-260. |
|15.||O' Donell HA. Experimental & clinical evidence of enhancement of BCG efficacy by adding Interferon a-2b. J Urol 1997, 157: (Abstract) 382. |
|16.||Engelmann U et al. Interferon a-2b instillation prophylaxis in superficial bladder cancer- a prospective controlled three-armed trial. Anti Cancer Drugs 1992; 33 (Suppl 3). |
[Table - 1], [Table - 2]