ARTICLES

ABSTRACT

Bladder malignancy is the 11th most common cancer worldwide with more than 2,00,000 new cases diagnosed
every year. 90% of these are superficial in nature.

Our aim in this study was to find the efficacy, safety and cost effectiveness of a low dose intravesical immunotherapy
with BCG (60mg) + Interferon-(X-2b (5 million IU) in prevention of its recurrances and prolong disease progression free
interval.

From Jan.'94 to Dec.'94, 100 patients of superficial TCC (T a' T 1) of urinary bladder with or without T is after
transurethral resection of the tumor underwent intravesical instillation of BCG (60mg) combined. with Interferon-a-2b
(5 million IU) weekly for eight weeks, fortnightly for eight weeks, monthly for eight weeks followed by maintenance
therapy at the end of 9th, 12th, 18th & 24th months with an average follow up of 60 months.

Results

At the end of 60 months of follow up showed 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 grade and stage.
Patient's tolerance was good and adverse reaction was low -19%.

Conclusion

This study has shown that a low dose combined therapy with BCG and Interferon-a-2b is not only safe, well tolerated,
cost effective as compared to high dose Interferon-a-2b when used as a single drug therapy, but also is highly effective
in prevention of tumor recurrences in 36%, maintaining superficial nature of the disease in another 44% with a disease
progression free interval of five years in 80% of cases.

INTRODUCTION

31adder cancer is the 11 th most common malignancy in the world with more than 2,00,000 new cases diagnosed every
year. In U.S.A. it is the 2nd most urological malignancy. About 90% of bladder carcinoma 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. Till date many intravesical instillation of drugs has been carried out for the past one and a half decade to prevent recurrences and prolong disease progression free interval. Though transurethral resection of these tumor 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 Irlterferon-a-2b .though less efficient as compared to BCG in term of preventing tumor recurrences has an advantage of being less toxic, a 2nd line of therapy after BCG recurrence, but is co: when used as a single drug therapy.

Since the mode of action of BCG and that of Interfer are different and in BCG recurrence cases, Interfer has shown good response and vice-versa, It was thou! that by combining low dose of BCG wish Interferon c can achieve less toxicity, would be more economical wt compared to Interferon as a single drug therapy with better efficacy in preventing recurrences and de disease progression free interval in these malignancy.

BCG is a biological response modifier when given intravesically produces a complex local immune reaction by producing local inflammation leading secretion of multiple cytokins including interleukin (It ll-12), Interferon, tumor necrosis factor with an increase CD4/CD8 T cell ratio.

Previous work has shown that BCG produces complete response rate of 55-60% but toxicity in the form of dysuria, frequency, haematuria, cystitis, spesis is : 35%. On the other hand the role of Interferon-a-2b t shown specially to augment the immuno modulate effect of BCG by amplifyjng the production of cytok such as IL-2, IL-12, Interferon gama apart from have direct inhibitory effect on the proliferation of tumor bladder' cancer cells. Intravesical Interferon-a- increases the cytotoxic activity of T-lymphocytes Natural Killer Cells (NKC) by increasing infiltration of the cells into bladder wall. Further more recent stud suggest that combination of these two drugs in a 10.. dose have shown better response rate than with eitl agent alone. With the above facts in mind we undertake a study of a low dose combined intravesi, immunotherapy using 60mg of BCG with 5 million IL Interferon-a-2b (Intron-A -Fulford Scherring) to achieve low toxicity, better efficacy in the form of longer tumor free recurrence rate and prolonged disease progress free interval keeping in view the cost factor.

MATERIALS & METHODS

Between Jan.'94 till Dec.'94, a total number of 1 patients diagnosed as superficial TCC of urinary bladder (T a' T 1) with or without associated Cis WI included in this study. This large number may explained due to the fact that our hospital is a large referral hospital. All these patients after a detail history, and clinical examination had routine haematological, Li Function Test (LFT) and renal function studies, before, being subjected to Transabdominal Ultrasonograp 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 Cystopanendoscopy (CPE) with biopsy as an outpatient procedure under Local Anaesthesia (LA) was dose in cases, not only to reach a histopathological diagnose but also to know the number, size and appearance of tumor mass.

Once the diagnosis and clinical staging was establish as T & T 1 transitional cell carcinoma (TCC) of urinary .

bladder, they were subjected to transurethral resection of tumor (TURT) under spinal anaesthesia/gene anaesthesia (SA/GA). All resections were done by 1 author only to have an uniformity. Meticulous care "' taken to completely resect the tumor mass along", base. so as to give enough tissue for histopathologi study.

Within one week of resection the histopathology report confirming the superficial nature of the tumor, the patients were subjected to intravesical instillation c million IU of Interferon-a-2b (Intron-A -Fulford Scherri diluted with 30 mi of physiological normal saline combination with 60mg of BCG mixed in 30 ml normal saline, under all aseptic measures through a red rubber catheter after evacuating the residual urine as a day care procedure weekly for eight weeks fortnightly for eight weeks, monthly for eight weeks the end of 9th, 12th, 18th and 24th months follow resection as maintenance dose -a total of 18 instillation in 2 years. Each instillation was for 2 hours duration during which the patient was asked to lie for half hour prone, suprine, left lateral and right lateral position sc to allow the drug to reach each quadrant of the bladder

.Fresh haemogram estimation was done at 1 beginning of each instillation

.During follow up periodic check cystoscopies Wl carried out during the therapy at the end of 3rd, E 9th, 12th month during the first year, six monthly next two years and yearly thereafter-

.In event of any recurrence the patients were subject to transurethral resection of tumor and histopathology proved it to be still low stage and I grade, the patients were continued in the sa schedule, i.e. for T a' T 1 stage.

.In case histopathology showed progression of disease to higher stage i.e. T 2' T 3' T 4 the patient were excluded from the study.

Response Criteria

Our result was evaluated as complete response, pal response or no response.

Complete response was defined as normal appearance of the bladder at follow up check cystoscopy with or
without biopsy with no tumor recurrence with urine cytology &. BTA stat being also negative. Tumor recurrences of
similar or lesser stage and grade on histopathology were designated as partial response while progression to higher
grade and stage was termed as no response. Toxicity was evaluated through patients report. observation by the investigators
and local systemic reaction.

OBSERVATION

The initial 121 patients of superficial TCC diagnosed in 1994 and who were expected to complete a five year follow up by
1999 were regularly followed up and included in this series. Out of the total number of 121 patients, there were 21
dropouts/deaths during follow up, leaving a total number of 100 patients who could actually complete a sixty months
follow up by 1999.

Eighty patients were male twenty were females, making the sex ratio as M:F :: 4:1.

Maximum incidence in female was in 5th decade, a decade earlier than their male counterpart.

All the 100 patients under study had at least one episode of haematuria, which was the commonest symptom. Associated symptoms were increased frequancy of micturition, anaemia, fever and weakness (Table I).

Table I

Clinical features of Patients with TCC

Out of the 100 patients, 36 patients were of stage T a' 56 patients stage T 1 and 8 patients of stage T 1 with Tis.

The WHO has proposed that TCC be divided into three grades (I, 11, 111) on the basis of urothelial architecture like cell size, pleomorphism, nuclear polarization and hyper chromatism; and the number of mitosis present. Basing of the above criteria our patient's histopathology reports were graded as Grade I, Grade II and Grade III as follows :

Grade I: Well differentiated cells with their fibrovascular stalk, thickened urothelium, having more than 7 cell layers with slight anaplasia, pleomorphism and mitotic figures with increased nuclear to cytoplasmic ratio and prominent nuclear membrane.

Grade II: Moderately differentiated cells with wider fibrovascular stalk, greater disturbance of the base to the surface cellular maturation, loss of cell polarity. Nuclear to cytoplasmic ratio is higher with more nuclear pleomorphism and prominent nucleoli.

Mitotic figures are frequent.

Grade III: Poorly differentiated cells without any differentiation of base to surface cellular maturation with marked pleomorphism, high nuclear to cytoplasmic ratio and more frequent mitotic figures.

A strong co-relation do exist between the stage and grade of the tumors. .

With above grading criteria, out of the 100 patients, 52 patients belonged to grade 1, 44 patients were of grade II and 4 patients were of grade III.

Higher the number, higher was the grade without any statistical significance.

Table II shows the relationship between the stage and grade of our 100 patients.

Table II

Stage and Grade of Tumors

History revealed 60% were ex-tobacco smoker, 24% were present smoker of tobacco, while 16% were non-smokers, thereby revealing tobacco smoking is a significant co-factor in developing cancer bladder.

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. 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. 16% 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% progression to higher stage at the end Qf 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, mayalgia and general weakness was also observed and one patient had hepatitis in whom the drug was withdrawn temporarily (Table III).

Table III

DISCUSSION The primary aim of this clinical trial was to establish the safety and efficacy of the low dose combination therapy of BCG + Interferon-a-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-a-2b is currently used with introduction of maintenance dose by many workers (Morales etal[1]).

Catalona et al[3] used high dose of Interferon as a monotherapy to achieve good result but it was costly. Similarly Glashan et al[4] and Distasi[5] using high dose of Interferon achieve good result.

Stricker p et al[6] have shown that the additive anitproliferative effect of BCG + Interferon-a.-2b on cell line derived from human bladder cancer cells. A combination of BCG + .lnterferon-a-2b at simulated clinical concentration had a similar anti proliferative effect to a double dose of BCG alone.

.BCG and Interferon-a-2b have a direct anti- proliferative effect on bladder tumor cells. In addition, these cells which are unresponsive to BCG previously, became susceptible to combined anti tumor activities of BCG plus Interferon. Our observation augment the clinical trials with combination of BCG & Interferon-a- 2b in the hope to reduce the BCG associated toxicity.

There is a considerable evidence to suggest that Interferon-a-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 patient 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 aim was to reduce toxic effect of the therapy with low dose of both the drugs was well perceived as

.only 19% of our patients had the adverse effect as compared to 40% by Lamm et al[1 0].

Finally by reducing the dose of both the drugs, the cost of the therapy was reasonable low.

.Our study has achieved a complete tumor free recurrence rate of 36% at the end of five years follow up with another 44% having superficial tumor recurrences. thereby giving a 80% disease progression free interval on five years follow up.

Table IV

Five year follow up of 100 Patients yearwise.

CONCLUSION

In conclusion our study has shown that a low dose combination immunotherapy of BCG + Interferon-a-2t is not only safe. economical but also very effective r 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 mandatvry.

REFERENCES

1. Mora/es A et al. )ntracavitary bacillus calmettee - Guerin in the treatment of superficial bladder tumors. J Uro11976; 116:180-183.

2. Morales A et al. Dose response of Baci\lus Calmette Guerin in the treatment of superficial bladder cancer. J Uro11992; 147:1256-58.

3. Catalona et al. Risk and benefits of repeated course of intravesical bacillus calmettee -Guerin therapy for superficial bladder cancer. J Uro11987; 137:220-24.

4. Glashen et al. A randomised controlled study of intravesical a-2b Interferon in carcinoma-in-situ of the bladder. J Uro11990; 144:658-661.

5. Distasi SM et al. Intralesional alpha Interferon in papillary superficial TCC of the baldder -A pilot study. Br J Uro11992; 422-426.

6. Stricker p et al. Bacillus Calmette Guerin + Intravesical Interferon-a-2b in patient with superficial bladder cancer. Uro11996; 48(b):957-61 , discussion 961-2.

7. Bercovich et al. BCG vs BCG+lnterferon-a-2b recombinate net tumor superficial della vesica. Arch Ital Uro11995; 67:257-260.

8. O'Donnell HA. Experimental and clinical evidence of enhancement of BCG efficacy by adding Interferon- a-2b. J Uro11997; 2, 157:382.

9. Engelmann U et al. Interferon-a-2binstillation prophylaxis in superficial bladder cancer -a prospective controlled three armed trial. Anti Cancer drugs Suppl 3 : 33; 1992.

10.Lamm DL et al. Long term results of intraveiscal therapy for superficial bladder cancer. Urol Clin North Am 1992; 19 : 573-580.