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RESEARCH ARTICLE
Year : 2004  |  Volume : 20  |  Issue : 2  |  Page : 24-28
 

Delayed cystectomy for T 1 G 3 TCC of urinary bladder managed initially by TURBT & intravesical immunotherapy (BCG + interferon) rationale & our result


Safdarganj Hospital, New Delhi, India

Correspondence Address:
N K Mohanty
C-II/124, Moti Bagh-I, New Delhi 110021
India
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   Abstract 

Objectives: Management of pT 1 G 3 TCC of urinary bladder is always a dilemma for urologists due to its high recurrence & disease progression rate.
We evaluated the role of conservative management for this subgroup with TURBT and intravesical immunotherapy; and delayed cystectomy for progressive disease with an aim to salvage bladder.
Patients & Methods: Between Jan.1996 to Dec.2002, 66 patients (15%) of pT 1 G 3 , out of a total 440 patients of superficial bladder cancer treated in this department were subjected to low dose BCG (40mg) and Interferon 3 million IU intravesically with maintenance therapy after complete TURBT and followed up for average 60 months. The mean tumor free interval was 26 months & 18 months in superficial recurrences & muscle progression disease respectively. Delayed cystectomy being preserved only for disease progression patients and the mean period of delayed cystectomy was 24 months (18-30 months).
Results: 19 patients (29%) had no tumor recurrence, 35 patients (53%) showed superficial recurrence and 12 patients (18%) progressed to higher stage at end of five year follow up thereby giving a disease progression free interval of 60 months in 82% of our patients. Five patients of disease progression group died due to metastatic disease process and 7 patients are alive after delayed cystectomy at the end of follow up. Side effects from intravesical therapy were confined to local irritative symptoms only.
Conclusion: Our data only confirms the benefit of adjuvant intravesical low dose immunotherapy in management of pT 1 G 3 tumor after TURBT with bladder salvage in 82% of patients, simultaneously not compromising the survival rate.


Keywords: Bladder tumors, BCG, pT 1 G 3 , Intravesical.


How to cite this article:
Mohanty N K, Saxena S, Goyal NK, Singh UP, Arora R P. Delayed cystectomy for T 1 G 3 TCC of urinary bladder managed initially by TURBT & intravesical immunotherapy (BCG + interferon) rationale & our result. Indian J Urol 2004;20:24-8

How to cite this URL:
Mohanty N K, Saxena S, Goyal NK, Singh UP, Arora R P. Delayed cystectomy for T 1 G 3 TCC of urinary bladder managed initially by TURBT & intravesical immunotherapy (BCG + interferon) rationale & our result. Indian J Urol [serial online] 2004 [cited 2019 Aug 19];20:24-8. Available from: http://www.indianjurol.com/text.asp?2004/20/2/24/37163



   Introduction Top


Urinary bladder cancer is the fourth most common malignancy among men and eighth most common malignancy among women [1] The incidence of bladder cancer has increased 36% in USA between 1956 to 1990 though motality rates declined 8% between 1980 to 1995 [2] In India its incidence has increased drastically in the last decade, thanks to rapid industrialization. At the time of initial diagnosis 75 to 80% of these malignancy are superficial in nature of which 70% are of stage Ta and 30% stage T1 [3] . Low grade non invasive tumors are mostly treated with resection and fulguration. Despite complete resection 75% of these patients will develop tumor recurrences in 5 years and 88% in 15 years time [4] This high rate of tumor recurrences and potential progression provides an opportunity to institute chemoprevention or prophylactic immunotherapy in their management. Progression from superficial to deep muscle invasion occurs in 15-20% of these patients. [5],[6]

Stage T1 disease irrespective of grade has demonstrated the biological ability to invade and progress in 29%. [7] Prostatic urethral involvement and Cis carries a high risk factor of progression and poor prognosis and should be treated aggressively.

The urologist faces a dilemma while managing pT 1 G 3 tumors. Though pT, that involves lamina propria is classified as superficial bladder cancer; the recurrence and progression pattern in this subgroup particularly with high grade III TCC is significantly different from true superficial disease. Patients with pT 1 G 3 disease have 10 times the chance of muscle invasion and death than from Ta tumors of same grade.

The recurrence rate of pT 1 G 3 tumors is 4.08% as compared to 1.1% in pT1G1-2 tumors, Jakse [8]

This subgroup p T 1 G 3 being at high risk puts an urologist in dilemma as to whether to treat with early cystectomy or continue with conservative management with trans urethral resection of bladder tumor (TURBT) and intravesical immunotherapy. Though historically early cystectomy for pT 1 G 3 tumors had yielded good results but currently the emphasis is on bladder preservation. Various authors have reported the success and failure in the management of pT 1 G 3 tumors using conservative measures and delayed cystectomy. The author advocates initial conservative management, and delayed cystectomy for progressive disease in this subgroup and presents his work with data in support of it with literature review.


   Patients & Methods Top


Between Jan.1996 to Dec.2002, a total number of 440 superficial bladder cancer were treated in Urology department of our Institute. A thorough diagnosis protocol consisting of urine cytology for malignant cells, NMP22, trans abdominal ultrasound of kidney, ureter & bladder area, CT abdomen and cystoscopy with biopsy was done in all patients for clinical staging. Out of these 66 patients (15%) were initially reported to be pT 1 G 3 tumors histologically and confirmed on review by one single oncopathologist of Indian Council of Medical Research (ICMR), Pathology department. 33 patients had tumors on lateral wall (Rt.18 & Lt.15), 12 on posterior wall, 10 behind bladder neck and 5 patients had tumors in dome. 5 tumors were of size less than 1cm, 49 tumors 1-5cm and 12 tumors more than 5cm. This subgroup of 66 patients (15%) of pT 1 G 3 after clinical staging and evaluation underwent complete transurethral resection of the bladder tumor (TURBT) followed by intravesical instillation with BCG (40mg) + Interferon -2b (3 million IU) (Roferon) one week after TURBT following histopathological confirmation. None of these patients had prostatic urethral involvement or associated Cis.

All patients had intravesical instillation of a low dose combination of BCG (40mg) (Danish 1331 strain) along with Interferon -2b (3MIU) (Roferon) mixed in 60ml of normal saline weekly for six weeks followed by three weekly instillation after cystoscopy at the end of 3 rd , 6 th , 9 th , 12 th month for first year and every six monthly thereafter as maintenance therapy. Each instillation was for a period of two hours duration, the patient lying in four different positions for half an hour each. Any tumor recurrences on follow up cystoscopy were subjected for TURBT In those patients in whom subsequent histology of tumor recurrences showed progression of disease were excluded from the protocol and subjected to radical cystectomy with urinary diversion. If recurrences were still superficial then intravesical immunotherapy was continued as per schedule.

Any side effects observed local or systemic were recorded.

Average follow up period was 60 months (42-78 months). Follow up included urine for cytology,

Ultrasonography of abdomen and cystoscopy.


   Result Top


  • Average age group of our patients was 58 years (32 to 84 years).
  • Male to female ratio was 5:1.
  • More than 70% of our patients were from urban background with no significance seen in dietary habit in relation to the disease development.
  • More than 70% of patients had a history of tobacco smoking for more than 10 years.
  • Out of 66 patients of pT 1 G 3 treated with TURBT followed by intravesical immunotherapy with low dose BCG (40mg) + Interferon -2b (3MIU), at the end of median 60 months follow up, 19 patients (29%) showed no recurrences, 35 patients (53%) showed superficial recurrences i.e. not muscle invasive while 12 patients (18%) showed muscle invasive recurrence who were subsequently subjected to radical Cystectomy with urinary diversion. Out of these 12 patients undergoing cystectomy, 7 patients are alive at the end of 5 years follow up and five have died due to metastatic disease.
  • Our result was analyzed for time to first recurrence, time to first disease progression and survival rate.
  • The average time to first tumor recurrence that was non invasive was 26 months and average time to first recurrence which showed progression to muscle invasive was 18 months.
  • Out of 35 patients who showed superficial tumor recurrences, subsequent histology showed 5 patients were T 1 G 1r 10 patients were T 1 G 2 while 20 patients were T 1 G, histologically. All these patients were managed subsequently by TURBT and maintenance intravesical immunotherapy as per schedule.
  • All the 12 patients who showed muscle invasive disease underwent delayed radical Cystectomy with urinary diversion. The average period in delay in their surgery was 24 months (18-30 months) in this group. During the follow up period, 5 patients died of metastatic disease while rest of seven patients were still alive at the end of 60 months follow up. Histologically all these 12 patients revealed to be T 2 G 3 (7 patients) and T 3 G 3 (5 patients) None had metastatic lymphadenopathy or distant metastasis at the time of surgery. All the 5 patients who died subsequently were pT 3 G 3 histologically.
  • Side effects were minimal, less than 10%. The commonest side effect being dysuria, frequency and urgency due to local cystitis. Haematuria was seen in a few cases. None of ours patients had BCG sepsis, granulomatous prostatitis or military tuberculosis.



   Discussion Top


Although included in non invasive superficial bladder cancer group pT 1 G 3 is a distinct subgroup because of their high rate of recurrence and disease progression. The aim of treatment in this subgroup is to salvage the bladder without compromising the survival rate. Our justification for conservative management with delayed cystectomy in this subgroup is based on our satisfactory result supported by international literature as follows

  • Less than 20% of patients of pT 1 G 3 tumors are detected in routine urology practice.
  • In 45% of these patients muscularis mucosae cannot be identified by best of pathologist. [9] Therefore there is always a tendency of overstaging of these tumors by primary pathologist initially.
  • Identifying the subset of pT 1 G 3 who are at a risk of disease progression is very difficult and the progression rate again is dependant on depth of tissue invasion. [Table 2]
  • Osterlinck (1993) [10] in his study (EORTC) review has shown that out of 96 cases of T 1 stage disease initially reported by local pathologist, 51 patients (53%) were Ta stage by central review pathologist.
  • Similarly Tosoni (1999) reviewed in Swiss group study showed out of 235 T1 diagnosed by local pathologists, 80 patients (35%) were Ta stage when reviewed.
  • Kurth K (1997) showed that out of 100 patients of T1 diagnosed by local pathologist, 50 patients (50%) were Ta stage when reviewed.


This only proves that all initially diagnosed pT 1 G 3 disease should be reviewed before any treatment as more than 50% overstaging is done, therefore subjecting all initially diagnosed pT,G 3 tumors for early cystectomy without review will lead to over treatment for more than 50% with associated risk of morbidity and mortality who could otherwise be managed conservatively.

In our series all 66 patients diagnosed as pT,G 3 were accepted only after second pathologist review report confirmed the same.

Again depth of invasion of tumor also predicts the staging and prognosis. If the depth of tumor invasion is < 1.5mm then only 44% can be pT,G 2 while if depth of invasion is > 1.5mm then 95% can be pT,G 3 type. Review of literature of J I G, tumors, disease progression on an average is 28% (23-34) of this subgroup would progress to muscle invasive stage after a mean follow up of 6.5 years (4-9 years).

Adjuvant intravesical therapy decrease the. frequency of recurrence, compared to TURBT alone in superficial bladder cancer. [11],[12],[13],[14],[15] Herr & Landone in 1998 observed that significant decrease in both recurrences and local progression rate when treated with BCG following TURBT. Another randomized study of this high risk pT 1 G 3 TOO with TURBT & BCG with maintenance therapy showed no tumor evidence in 50% and 34% suffered cancer related deaths after a median follow up of 90 months.

Long term follow up studies have consistently demonstrated prolonged protection from tumor recurrences by BCG [16],[17],[18] as well as increasing evidence to suggest that optimal maintenance BCG intravesical immunotherapy also reduces tumor progression and mortality. [16],[17],[18],[19] Many clinical studies comparing surgery alone with intravesical BCG immunotherapy demonstrated a highly significant advantage of BCG treatment. [19],[20],[21],[22],[23],[24]

Cookson and Sarosdy [25] have demonstrated effectiveness of BCG in high risk T1 patients in their trial. 91% of those treated with intravesical BCG immunotherapy were free of disease at a mean follow up of 59 months. BCG effectively reduces tumor progression has been demonstrated [17],[19],[26] showing statistically significant reduction in progression to muscle invasive or metastasis. A controlled trial from Sloan Kettering Memorial Hospital study showed persistent reduction in both tumor recurrence & progression after 10 years of follow up.

Lamn [27] is of the opinion that use of BCG has effectively spared cystectomy in many pT1G3 disease patients.

Herr [26] remarks that cystectomy rate has reduced from 42% to 26% in high risk pT 1 ,G 3 patients after using intravesical BCG.

The effectiveness of maintenance immunotherapy in reducing tumor progression in high risk pT 1 G 3 who failed to prior intravesical chemotherapy is significant after use of BCG Witjes(1993). [29]

Data suggest that maintenance therapy with BCG improves long term results by increasing long term disease free status from the expected 65% to 83%. [16] In another 391 randomized patients trial, the excelled 86% survival at 4 years observed with induction therapy was improved to 92% in patients receiving maintenance BCG. [30]

Proponents of delayed cystectomy for pT,G 3 tumors have shown median survival rate in 67% on a five year follow up (Stockle, Amiling, Freman). In contrasts proponents of early cystectomy [31],[32] for recurrences give a five year survival of 60% when delayed cystectomy are performed which only strengths the arguments in support of delayed cystectomy in this subgroup.

Complete TURBT followed by BCG therapy for pT 1 G 3 resulted in an over all progression free rate that supports bladder sparing strategy with close monitoring.

If Cystectomy is done at the time of initial diagnosis of pT 1 G 3 tumors then perhaps half of the patient will be over treated; when there is a delay then 60% patients will retain bladder Borkowski. [34]

Immediate Cystectomy is the best chance for cure in those 15% of patients of pT 1 G 3 at risk of cancer progression the pT 1 G 3; simultaneously is an over treatment for more than 85% of these malignancy.

We advocate instillation of low dose BCG (40mg) along with Interferon -2b (3MIU) as this combination therapy not only reduces effectively the toxicity rate of BCG (120mg) monotherapy but also is cost effective and results in reducing tumor recurrence rate and disease progression interval immensely as both these drugs act in synergism. Our result with a median follow up of 5 years have shown no tumor recurrences in 29%, superficial recurrence in another 53% thereby giving an overall disease progression free period of 60 months in 82% of our patients. Only 18% of our patient progressed to muscle invasive stage requiring cystectomy. Our high rate of 82% of disease progression free period of sixty months may be attributed to use of maintenance therapy that we advocate. Progression to high grade in our series is comparable to that of other.

  • Side effects in our session was minimal 8% limited only local irritative symptoms only. This is mostly because of use of low dose of BCG.
  • Therefore we advocate that all pT 1 G 3 without associated Cis or prostatic invasion should be initially treated conservatively with periodic maintenance therapy with strict surveillance by regular cystoscopy, urine for cytology and bladder biopsy if required keeping in view the risk factors, simultaneously not compromising in survival rate with control of the disease and provide a good quality of life. By this bladder salvage can be achieved in more than 82% of these patients for five years without any risk & does not delay necessary Cystectomy in those patients who fail to respond to conservative therapy with control of the disease and provide a good quality of life.



   Conclusion Top


Our study confirms and justifies initial conservative management with TURBT+ adjuvant intravesical therapy with low dose BCG & Interferon in patients with pT 1 G 3 TCC of urinary bladder as it is safe & effective adjuvant therapy in this subgroup with delayed cystectomy for disease progressive patients with high rate of bladder conservation, good quality of life, simultaneously not compromising in survival rate.

 
   References Top

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2.Cohen SM, Johansson SL. Epidemiology and etiology of bladder cancer. Urol Clin North Amer. 1992; 19:421-428.  Back to cited text no. 2    
3.Ro JY, Staerkel GA, Ayala AG. Cytologic and histologic features of superficial bladder cancer (Review). J Urol Clin North Amer. 1992; 19:435-449.  Back to cited text no. 3    
4.Lamm DL, Griffith JG. Intravesical Therapy : Does it affect the natural history of bladder cancer? Semin Urol 1992; 10:39-44.  Back to cited text no. 4    
5.Lamm DL, Griffith JG Jr, Daly JJ. Noninvasive papillary carcinoma of the bladder associated with carcinoma in situ. J Urol 1976; 116:575-580.  Back to cited text no. 5    
6.Lytzeyer W, Rubben H, Dahm H. Prognostic parameters in superficial bladder cancer : an analysis of 315 cases. J Urol 1982; 127:250-252.  Back to cited text no. 6    
7.Bostwick DG. Natural history of bladder cancer. J Cell Biochem. 1992; 161:31-38.  Back to cited text no. 7    
8.Jakse G, Loid LW, Seeber G. Stage T1G3 TCC of bladder : an unfavourable tumor. J Urol 1987; 137:39-43.  Back to cited text no. 8    
9.Smits G, Debruyne F, Witjes JA, et al. Microstaging of pTl TCC of bladder identification of subgroups with distinct risk of progression. Urol 1998; 52:1009-14.  Back to cited text no. 9    
10.Oosterllinck W, Kurth KH, Schroder F, Bultinck J, Hammond B, Cylvester R and Members of the European Organization for Research and Treatment of Cancer Genitourinary group. A prospective European organization of research and treatment of cancer genitourinary group randomized trial comparing transurethral resection followed by a single intravesical instillation of epirubicin or water in a single state Ta, T1 papillary carcinoma of the bladder. J Urol 1993; 149:749-752.  Back to cited text no. 10    
11.Lamm DL. BCG vs adriamycin in the treatment of TCC in situ a South-West oncology group study. J Urol 1985; 133:A283.  Back to cited text no. 11    
12.Debruyne FJG, Vander Meyden PM, BCG versus Mitomycin C intravesical therapy in patients with superficial bladder cancer : first results of a randomized prospective trial. J Urol 1987; 137:179A.  Back to cited text no. 12    
13.Morik Lamm DL, Crawford ED. A trial of Bacillus Calmette-Guerin vs adriamycin in superficial bladder cancer. SWOG study Urol Int. 1986; 332:1.  Back to cited text no. 13    
14.Jauhiainen K, Rintala E, Alfthan 0. Immunotherapy (BCG) vs. chemotherapy (MNC) in intravesical treatment of superficial bladder cancer. Int. Society of Urology report. Immunotherapy of Urological tumors. Edinburgh: Churchill LivingStru 1990; 2:13.  Back to cited text no. 14    
15.Martinez-Piffiew JA, J Lean et al. BCG vs Doxorubicin vs thiotepa : A randomized study in 202 patients with superficial bladder cancer. J Urol 1990; 143:502.  Back to cited text no. 15    
16.Lamm DL. Long term results of intravesical therapy for superficial bladder cancer. In Lamm DL, ed. The Urologic Clinics of North America, Philadelphia, PA: W. B. Saunders Co. 1992; 19:573-580.  Back to cited text no. 16    
17.Nadler RB, Catalona WJ, Hudson MA, Ratliff TL. Durability of tumor-free response for intravesical bacillus Calmette Guerin therapy. J Urol 1994; 152(2 Pt 1): 367-373.  Back to cited text no. 17    
18.Herr HW. Transurethral resection and intravesical therapy of superficial bladder tumors. In Fair WR, ed. The Urologic Clinics of North America, Philadelphia, PA: W.B. Saunders Co. 1991; 18:525-528.  Back to cited text no. 18    
19.Lamm DL. Bacillus Calmette-Guerin immunotherapy for bladder cancer. Journal of Urology 1985; 134:40-47.  Back to cited text no. 19    
20.Herr HW, Pinsky CM, Whitmore WF, et al. Experience with intravesical Bacillus Calmette-Guerin therapy of superficial bladdertumors. Urology 1985;25:119.  Back to cited text no. 20    
21.Herr HW, Pinsky CM, Whitmore WF, et al. Long-term effect of intravesical Bacillus Calmette-Guerin on flat carcinoma in situ of the bladder. J Urol 1986; 135:265.  Back to cited text no. 21    
22.Pagano F, Bassi P, Milani C, et al. A low dose bacillus Calmette-Guerin regimen in superficial bladder cancer therapy: Is it effective? J Urol 1991; 146:32.  Back to cited text no. 22    
23.Melekos MD, Chionis H, Pantazakos A, Fokaefs E, Paranychianakis G and Dauaher H. Intravesical Bacillus Calmette-Guerin immunoprophylaxis of Superficial Bladder Cancer : Results of a controlled prospective trial with modified treatment schedule. J Urol 1993; 149:744.  Back to cited text no. 23    
24.Krege S, Giani G, Meyer R, et al. A randomized multicenter trial of adjuvant therapy in superficial bladder cancer : transurethral resection only versus transurethral resection plus mitomycin versus transurethral resection plus Bacillus Calmette-Guerin. J Urol 1996; 156:962-6.  Back to cited text no. 24    
25.Cookson, MS, Sarosdy MF Management of stage T1 superficial bladder cancer with intravesical bacillus Calomette-Guerin therapy. Journal of Urology 1992; 148:797-801.  Back to cited text no. 25    
26.Herr HW, Laudone VP, Badalament RA, et al. Bacillus Calmette-Guerin therapy alters the progression of superficial bladder cancer. J Clin Oncol 1988; 6:1450-1455.  Back to cited text no. 26    
27.Lamm DL, Blumenstein BA, Carwford ED, Montie JE et al. A randomized trial of intravesical doxorubicin and immunotherapy with Bacilli Calmette-Guerin for transitional cell carcinoma of the bladder. New Engl J Med 1991; 325(17):1205-1209.  Back to cited text no. 27    
28.Witjes JA, Vander Meijden AP, Witjes JP, et al. Randomized prospective study comparing intravesical instillations of Mitomycin-C, BCG-TICE, and BCGRIVM in Pta-Ptl tumors and primary carcinoma in situ of the urinary bladder. Dutch South-East Cooperative Group. EurJ Cancer 1993; 29A:1672-1676.  Back to cited text no. 28    
29.Lamm DL. BCG in perspective : advances in the treatment of superficial bladder cancer. Eur Urol 1995; 27 (Suppl 1):2-8.  Back to cited text no. 29    
30.Labrek T, Gaudez F, Herve JM et al. Low dose BCG instillation in the treatment of stage T1G3 bladder tumors; recurrences, progression & success. Eur Urol 1998; 34:67-72.  Back to cited text no. 30    
31.Ovesen H, Poulsen AL, Steven K. Intravesical bacillus Calmette-Guerin with Danish Strain for treatment of carcinoma in-situ of the bladder. Br J Urol 1993; 72:744-8.  Back to cited text no. 31    
32.Pham HT, Soloway MS. High risk superficial bladder cancer intravesical therapy for T1G3 TCC of urinary bladder. Semin Urol Oncol 1997; 15:147-52.  Back to cited text no. 32    
33.Pansadoro V, Emilozzi P, Defidio D et al. Bacillus calmette Guerin in the treatment of stage TI Grade III TCC of the bladder long term results. J Urol 1995; 154:2054.  Back to cited text no. 33    
34.Borkowski A. Superficial bladder cancer T1G3 the choice of treatment. J of Urol 2002; 89-b, 623-627.  Back to cited text no. 34    




 

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