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UROSCAN
Year : 2010  |  Volume : 26  |  Issue : 1  |  Page : 153-155
 

Is single-dose postoperative intravesical gemcitabine effective to prevent recurrence in patients with non-muscle invasive bladder cancer?


Department of Urology, C. S. M. Medical University, Erstwhile (King George Medical University), Lucknow - 226 003, Uttar Pradesh, India

Date of Web Publication23-Mar-2010

Correspondence Address:
Apul Goel
Department of Urology, C. S. M. Medical University, Erstwhile (King George Medical University), Lucknow - 226 003, Uttar Pradesh
India
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Source of Support: None, Conflict of Interest: None


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How to cite this article:
Jain A, Goel A, Sankhwar S N. Is single-dose postoperative intravesical gemcitabine effective to prevent recurrence in patients with non-muscle invasive bladder cancer?. Indian J Urol 2010;26:153-5

How to cite this URL:
Jain A, Goel A, Sankhwar S N. Is single-dose postoperative intravesical gemcitabine effective to prevent recurrence in patients with non-muscle invasive bladder cancer?. Indian J Urol [serial online] 2010 [cited 2020 Oct 22];26:153-5. Available from: https://www.indianjurol.com/text.asp?2010/26/1/153/60471

Bohle A, Leyh H, Frei C, Kuhn M, Tschada R, et al. Eur Urol 2009;56:495-503. Single Postoperative Instillation of Gemcitabine in Patients with Non-muscle-invasive Transitional Cell Carcinoma of the Bladder: A Randomized, Double-blind, Placebo-controlled Phase III Multicentre Study.



   Summary Top


The authors conducted a randomized, double-blind, placebo- controlled study from January 2004 to June 2005 at 24 centers in Germany and Turkey to determine the role of intravesical gemcitabine as a single postoperative instillation in non-muscle invasive bladder cancer [pTa/pT1, G1-3] (NMIBC). Based on previous studies to prove the power of difference on log rank test, 355 patients were randomized; 328 of them underwent transurethral resection (TUR) and received instillations (166 gemcitabine, 162 placebos). Patients with no malignancy, ≥ pT2 tumors, CIS or with intraoperative complications were excluded. A single postoperative 30- 40 minute instillation of gemcitabine 2000 mg/100 ml or 100 ml of saline (placebo) followed by continuous bladder irrigation for ≥20 hrs was done. Other treatments like second TUR, adjuvant BCG instillations were allowed if indicated. Results were measured in terms of recurrence-free survival (RFS), type of recurrence and adverse events. Out of 328 patients included, 248 were found eligible for the study. In gemcitabine arm 76.6% were male and median age was 65 years while in placebo arm 83.1% were male and median age was 67 years. Both arms in this study were comparable in tumor size, grade, recurrence and adjuvant BCG instillations. After a median follow-up of 24-months, 94 recurrences and 11 deaths were noted. Twelve-month RFS was 77.7% in the gemcitabine group and 75.3% in the placebo group. There were no significant group differences in hazard ratio and log rank test.

Authors concluded that immediate single instillation of gemcitabine after TUR was not superior to placebo in terms of RFS. The authors speculate that the high RFS noted in this study could be due to long postoperative saline irrigation and improved TUR techniques.


   Comments Top


Non-muscle-invasive bladder cancer comprises 70-80% of bladder cancers at initial diagnosis and is primarily managed by TURBT. The probability of recurrence is about 60% within one year and 80% within five years. Risk of tumor progression to muscle invasion is about 17 to 45% in one to five years respectively. [1]

To decrease the risk of recurrence, single postoperative instillation of chemotherapeutic agents has been found effective and decreases recurrence by about 39% after a median follow-up of 3.4 years. [2] Chemo-resection of residual tumor after an incomplete TUR and destroying circulating tumor cells that could implant at the site of resection are the rationale behind the use of immediate instillation of chemotherapeutic agents. Commonly used drugs are mitomycin C, doxorubicin, epirubicin and Thiotepa. [3] If bladder perforation suspected/obvious then immediate instillation is avoided.

Gemcitabine with cisplatin is commonly used for systemic therapy of advanced invasive-bladder cancer and yields response rates of 23-28%. Gemcitabine has low molecular-weight in comparison to mitomycin C and doxorubicin that helps in the penetration of bladder mucosa with beneficial effects on early invasive bladder cancer.

In experimental murine bladder models, gemcitabine prevented tumor cell implantation and tumor outgrowth when given within 30 minutes after coagulation of the bladder mucosa and instillation of tumor cell suspension. [3] In several phase I and phase II clinical studies, intravesical gemcitabine was found effective and safe at doses of 2000 mg in 50 or 100 ml of saline (20 or 40 mg/ml). Instillation time ranged from 30 minutes to 2hrs. [4]

According to authors the possible explanation behind failure is that gemcitabine is a pyrimidine analogue acting phase-specifically during DNA-replication only and a single instillation of 30-40 minutes duration might have been too short to catch all tumor cells during DNA replication. In cell culture systems, the effect of gemcitabine on deoxynucleotide triphosphate pool depletion occurred during the first 30 minutes and reached the maximum effect within two hours while in mice it was only 30 minutes. [5]

Gemcitabine showed a good response when repeated instillation schedule was used. Gardmark et al., [6] randomized patients to a single gemcitabine instillation (2000 mg/100 ml of saline) or two gemcitabine instillations/week for three weeks or one gemcitabine instillation/week for six weeks. After nine weeks, 10% of patients in the single-instillation group versus 40% and 44% in the multiple instillation groups were in complete remission, suggesting that only multiple dosing regimens were effective.

Intravesical gemcitabine showed little adverse effects like alopecia, pyrexia and procedural pain during the study. Further studies are required to prove the results of this study.

 
   References Top

1.Sylvester RJ, van der Meijden APM, Oosterlinck W, Witjes JA, Bouffioux C, Denis L, et al. Predicting recurrence and progression in individual patients with stage Ta T1 bladder cancer using EORTC risk tables: A combined analysis of 2596 patients from seven EORTC trials. Eur Urol 2006;49:466- 77.  Back to cited text no. 1      
2.Sylvester RJ, Oosterlinck W, van der Meijden A. A single immediate postoperative instillation of chemotherapy decreases the risk of recurrence in patients with stage Ta T1 bladder cancer: A meta-analysis of published results of randomized clinical trials. J Urol 2004;171:2186- 90.  Back to cited text no. 2      
3.Brocks CP, Buttner H, Bohle A. Inhibition of tumor implantation by intravesical gemcitabine in a murine model of superficial bladder cancer. J Urol 2005;174:1115-8.  Back to cited text no. 3      
4.Palou J, Carcas A, Segarra J, Duque B, Salvador J, Garcia-Ribas I, et al. Phase I pharmacokinetic study of a single intravesical instillation of gemcitabine administered immediately after transurethral resection plus multiple random biopsies in patients with superficial bladder cancer. J Urol 2004;172:485-8.  Back to cited text no. 4      
5.Heinemann V, Hertel LW, Grindey GB, Plunkett W. Comparison of the cellular pharmacokinetics and toxicity of 2', 2'-difluorodeoxycytidine and 1-beta-D-arabinofuranosylcytosine. Cancer Res 1988;48:4024- 31.  Back to cited text no. 5  [PUBMED]    
6.Gardmark T, Carringer M, Beckman E, Malmstrom PU; Intravesical Gemcitabine Study Group. Randomized phase II marker lesion study evaluating effect of scheduling on response to intravesical gemcitabine in recurrent stage Ta urothelial cell carcinoma of the bladder. Urology 2005;66:527-30.  Back to cited text no. 6      




 

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