Single post-operative instillation of gemcitabine does not seem to affect recurrence rates for high-grade non-muscle invasive bladder cancer. Gemcitabine is inferior to BCG for primary treatment of high-grade disease. Gemcitabine alone or in combination with other agents can be considered for bacillus Calmette-Guérin refractory high-grade disease if cystectomy is contraindicated or refused, with reported recurrence-free rates of 37-72% at 1 year. Gemcitabine administration is generally well-tolerated with mostly mild adverse effects.

1. HIGH RISK NMIBC: GEMCITABINE?
​Dr Mayank Mohan Agarwal
MBBS, MS, MRCS(Ed), ​DNB, M.Ch (PGIMER, Chandigarh)
VMMF and IAUA Fellowships Uro-Oncology, Pelvic Floor Reconstruction
(MSKCC, NY; UCLA, LA; WFUBMC, NC)​
Ex-Associate Professor of Urology (PGIMER, Chandigarh)
Consultant and Head of Urology
(Aster) Dr. Ramesh Cardiac and Multispecialty Hospitals Pvt. Ltd.
Guntur (AP), India

2. INTRODUCTION
• Gemcitabine: the ideal molecule?
• Immediate post-op
• For induction therapy: alone
• For induction therapy: with other agent
• Adverse effects
• Optimization of instillation: advances
• Conclusion

3. Gemcitabine: the ideal molecule?
• Antimetabolite (deoxycytidine analog)
• Gets incorporated in DNA and leads to apoptosis
• Why Gemcitabine for intravesical –
• 300D cutoff for absorption into bladder mucosa
Gemcitabine MMC Doxorubicin
299 389 589
G G
Ta
T1
Gontero P, Marini L, Frea B. Intravesical gemcitabine for superficial bladder cancer: rationale for a new treatment option. BJUI 2005

4. Gemcitabine: the ideal molecule?
• Antimetabolite (deoxycytidine analog)
• Gets incorporated in DNA and leads to apoptosis
• Why Gemcitabine for intravesical –
• Non-ionized form better absorbed into bladder mucosa ()
Gemcitabine MMC Doxorubicin
pKa 3.6 2.8 7.3
• Urine pH is suitable for gemcitabine and MMC
Gontero P, Marini L, Frea B. Intravesical gemcitabine for superficial bladder cancer: rationale for a new treatment option. BJUI 2005

5. Gemcitabine for immediate post-op
• Bohle et al 2009 (Eur Urol)
• n = 124, each group
• 2gm G / 100ml 35min
• f/b 20H irrigation
• Appx quarter recurrent, >2, T1
• Appx 10% G3
Bohle A, Leyh H, Frei C, etal. Single Postoperative Instillation of Gemcitabine in Patients with Non-muscle-invasive Transitional Cell Carcinoma of the Bladder: A Randomised, Double-blind, Placebo-controlled Phase III Multicentre
Study. Eur Urol 2009
P = NSP = NS P = NS

6. Gemcitabine for immediate post-op
• Bohle et al 2009 (Eur Urol)
• n = 124, each group
• 2gm G / 100ml 35min
• f/b 20H irrigation
• Appx quarter recurrent, >2, T1
• Appx 10% G3
Bohle A, Leyh H, Frei C, etal. Single Postoperative Instillation of Gemcitabine in Patients with Non-muscle-invasive Transitional Cell Carcinoma of the Bladder: A Randomised, Double-blind, Placebo-controlled Phase III Multicentre
Study. Eur Urol 2009
P = NS
0
10
20
30
40
50
60
70
80
90
overall low risk high risk
gemcitabine placebo
P = NSP = NS P = NS

7. Gemcitabine for immediate post-op
• Messing et al, 2018 (JAMA)
• n = 201 (GMB), 205 (PBO)
• 2gm G / 100ml 60min within 3hours
• No mandatory prolonged irrigation
• About a third recurrent
• About a quarter G3
Messing EM, Tangem CM, Seth PH, etal. Effect of Intravesical Instillation of Gemcitabine vs Saline Immediately Following Resection of Suspected Low-Grade Non–Muscle-Invasive Bladder Cancer on Tumor Recurrence SWOG
S0337 Randomized Clinical Trial. JAMA 2018;
P <0.05P <0.05 P = NS

8. Gemcitabine for immediate post-op
• Messing et al, 2018 (JAMA)
• n = 201 (GMB), 205 (PBO)
• 2gm G / 100ml 60min within 3hours
• No mandatory prolonged irrigation
• About a third recurrent
• About a quarter G3
Messing EM, Tangem CM, Seth PH, etal. Effect of Intravesical Instillation of Gemcitabine vs Saline Immediately Following Resection of Suspected Low-Grade Non–Muscle-Invasive Bladder Cancer on Tumor Recurrence SWOG
S0337 Randomized Clinical Trial. JAMA 2018;
0
10
20
30
40
50
60
70
80
90
100
overall low grade high grade
gemcitabine placebo
P <0.05P <0.05 P = NS

9. Single post-op instillation Gemcitabine alone does
not seem to affect recurrence rate for high grade
disease: no study focused on this group
• Single-dose intravesical
chemotherapy within 24
hours of TURBTc
 Gemcitabine (category 1) or
 Mitomycin (category 1)

10. Single post-op instillation Gemcitabine does not
seem to affect recurrence rate for high grade
disease: no study focused on this group

11. Single post-op instillation Gemcitabine does not
seem to affect recurrence rate for high grade
disease: no study focused on this group

12. Single post-op instillation Gemcitabine does not
seem to affect recurrence rate for high grade
disease: no study focused on this group

13. Single post-op instillation Gemcitabine does not
seem to affect recurrence rate for high grade
disease: no study focused on this group

14. Gemcitabine vs BCG for primary G3 NMIBC
• Porena et al. Urol Int 2010
• N = 32 in each arm
• BCG 500m in 50ml / 2H Lamm regimen
• Gemcitabine 2000mg in 50ml / 1H Lamm- like regimen
Porena M, Del Zingaro M, Larezzi M, et al. Bacillus Calmette-Guérin versus Gemcitabine for Intravesical Therapy in High-Risk Superficial Bladder Cancer: A Randomised Prospective Study. Urol Int 2010
0
10
20
30
40
50
60
BCG Gemcitabine
recurrence

15. Gemcitabine vs BCG for primary G3 NMIBC
• Porena et al. Urol Int 2010
• N = 32 in each arm
• BCG 500m in 50ml / 2H Lamm regimen
• Gemcitabine 2000mg in 50ml / 1H Lamm- like regimen
Porena M, Del Zingaro M, Larezzi M, et al. Bacillus Calmette-Guérin versus Gemcitabine for Intravesical Therapy in High-Risk Superficial Bladder Cancer: A Randomised Prospective Study. Urol Int 2010
0
10
20
30
40
50
60
BCG Gemcitabine
recurrence

16. Gemcitabine is inferior to BCG for primary high
grade NMIBC
BCG (preferred)
or
Intravesical chemotherapyj
or
observation
BCG (preferred) (category 1)
or
Intravesical chemotherapyj
or
Observation in highly select cases

17. Gemcitabine is inferior to BCG for primary high
grade NMIBC

18. Gemcitabine for BCG / other treatment
refractory high grade NMIBC
• Shelly et al, 2012. Cochrane systematic review (published in BJUI)
• 521 references screened 
• 6 RCT’s
• 27 observational studies
• Heterogeneous study-designs
• Only one study solely for high grade disease
Shelley MD, Jones G, Cleves A, et al. Intravesical gemcitabine therapy for non-muscle invasive bladder cancer (NMIBC): a systematic review. BJUI 2012

19. Gemcitabine as sole agent : observational
Shelley MD, Jones G, Cleves A, et al. Intravesical gemcitabine therapy for non-muscle invasive bladder cancer (NMIBC): a systematic review. BJUI 2012
(25 G3, 11 CIS, 39 BCG refractory) 56-68% RF

20. Gemcitabine as sole agent : observational
Shelley MD, Jones G, Cleves A, et al. Intravesical gemcitabine therapy for non-muscle invasive bladder cancer (NMIBC): a systematic review. BJUI 2012
(25 G3, 11 CIS, 39 BCG refractory) 56-68% RF
Excerpts
• Most studies in BCG refractory disease
• Heterogeneous groups
• Heterogeneous schedules
• Significant proportion high grade
• 21 – 65 % recurrence-free at 1 year

21. Shelley MD, Jones G, Cleves A, et al. Intravesical gemcitabine therapy for non-muscle invasive bladder cancer (NMIBC): a systematic review. BJUI 2012
47.5
12.5
72
61
Gemcitabine as sole agent : RCT

22. Shelley MD, Jones G, Cleves A, et al. Intravesical gemcitabine therapy for non-muscle invasive bladder cancer (NMIBC): a systematic review. BJUI 2012
47.5
12.5
72
61
Gemcitabine as sole agent : RCT
Excerpts
• For BCG refractory disease Gemcitabine is superior to
• Another course of BCG
• MMC
• Recurrence free – 47 – 72%

23. Gemcitabine + MMC
Cockerill et al 2016 27 BCG refractory 1g gemcitabine plus 40mg
MMC weekly x 6-8
37% recurrence free
15.2m rec free survival
Lightfoot et al 2014 37 BCG refractory 1g gemcitabine plus 40mg
MMC weekly x 6-8 then
monthly x 12m
48% recurrence free 12m
38% recurrence free 24m
Shelley MD, Jones G, Cleves A, et al. Intravesical gemcitabine therapy for non-muscle invasive bladder cancer (NMIBC): a systematic review. BJUI 2012; Lightfoot AJ, Breyer BN, Rosewear M, et al. Multi-institutional analysis of
sequential intravesical gemcitabine and mitomycin C chemotherapy for non–muscle invasive bladder cancer. Urol Oncol 2014; Cockerill PA, Knoedlar JJ, Frank I, et al. Intravesical gemcitabine in combination with mitomycin C
as salvage treatment in recurrent non-muscle-invasive bladder cancer. BJUI 2016

24. Gemcitabine + Docetaxel
Cockerill et al 2016 27 BCG refractory 1g gemcitabine plus 40mg
MMC weekly x 6-8
37% recurrence free
15.2m rec free survival
Lightfoot et al 2014 37 BCG refractory 1g gemcitabine plus 40mg
MMC weekly x 6-8 then
monthly x 12m
48% recurrence free 12m
38% recurrence free 24m
Shelley MD, Jones G, Cleves A, et al. Intravesical gemcitabine therapy for non-muscle invasive bladder cancer (NMIBC): a systematic review. BJUI 2012; Lightfoot AJ, Breyer BN, Rosewear M, et al. Multi-institutional analysis of
sequential intravesical gemcitabine and mitomycin C chemotherapy for non–muscle invasive bladder cancer. Urol Oncol 2014; Cockerill PA, Knoedlar JJ, Frank I, et al. Intravesical gemcitabine in combination with mitomycin C
as salvage treatment in recurrent non-muscle-invasive bladder cancer. BJUI 2016; Milbar N, Kates M, Chappidi, et al. Oncological Outcomes of Sequential intravesical Gemcitabine and Docetaxel in Patients with Non-Muscle
Invasive Bladder Cancer. Bladder cancer 2017; Steinberg RL, Thomas LJ, O’Donnel MA, Nepple KG. Sequential Intravesical Gemcitabine and Docetaxel for the Salvage Treatment of Non-Muscle Invasive Bladder Cancer.
Bladder Cancer 2015
Milbar et al 2017 25 BCG refractory 1g gemcitabine plus
37.5mg DOCE weekly x 6-
8 +/- maintenance
43% recurrence free 12m
24% recurrence free 24m
Steinberg et al 2015 41 BCG refractory 1g gemcitabine plus
37.5mg DOCE weekly x 6
54% recurrence free 12m
34% recurrence free 24m

25. Gemcitabine alone or in combination can be
considered in BCG refractory high grade
disease if cystectomy is contraindicated or
refused
Change
intravesical
agenti,p
Change intravesical agenti,p

26. Gemcitabine alone or in combination can be
considered in BCG refractory high grade
disease if cystectomy is contraindicated or
refused
? CONTRARY TO EVIDENCE

27. Gemcitabine alone or in combination can be
considered in BCG refractory high grade
disease if cystectomy is contraindicated or
refused

28. • Several dose finding studies – animal  humans
• Upto 2000mg / 50ml concentration
• Upto 2 hours indwelling
• Well tolerated –
Minimal and transient plasma levels
• Do not “push” but instill gently
• Do not instill if perforation
Adverse effects
Dalbagni G, Russo P, Sheinfeld J et al. Phase I trial of intravesical gemcitabine in bacillus Calmette-Guerin-refractory transitional-cell carcinoma of the bladder. J Clin Oncol 2002; 20: 3193–8; De Berardinis E, Antonini G, Peters GJ et
al. Intravesical administration of gemcitabine in superficial bladder cancer: a phase I study with pharmacodynamics evaluation. BJU Int 2004; 93: 491–4; Witjes JA, van der Heijden AG, Vriesema JL, Peters GJ, Laan A, Schalken J.
Intravesical gemcitabine. A phase 1 and pharmacokinetic study. Eur Urol 2004; 45: 182–6

29. Adverse effects
• Overall 15-25%,
• mostly grade 1
• few grade 2
• >grade 2 exceedingly rare
• Dysuria, Frequency, Bladder pain
• Hematuria
• Nausea and vomiting
• Myelosuppression
Dalbagni G, Russo P, Sheinfeld J et al. Phase I trial of intravesical gemcitabine in bacillus Calmette-Guerin-refractory transitional-cell carcinoma of the bladder. J Clin Oncol 2002; 20: 3193–8; De Berardinis E, Antonini G, Peters GJ et
al. Intravesical administration of gemcitabine in superficial bladder cancer: a phase I study with pharmacodynamics evaluation. BJU Int 2004; 93: 491–4; Witjes JA, van der Heijden AG, Vriesema JL, Peters GJ, Laan A, Schalken J.
Intravesical gemcitabine. A phase 1 and pharmacokinetic study. Eur Urol 2004; 45: 182–6

30. • Safe practices are paramount
• Prepare in 50ml
• Catheterize atraumatically
• Instill not push
• Retain for 1h
• Alkalanize urine night before treatment
Gemcitabine is safe for intravesical admin.

31. Advances in drug delivery
• To improve penetration
• Electromotive drug administration (EMDA)
• Thermochemotherapy (Synergo)
• To improve retention
• Nanoparticles
• Side effects higher
• Efficacy higher
van der Heijden AG, Kiemeney LA, Gofrit ON, et al. Preliminary European results of local microwave hyperthermia and chemotherapy treatment in
intermediate or high risk superficial transitional cell carcinoma of the bladder. Eur Urol 2004;46:65–72.; Di Stasi SM, Giannantoni A, Stephen RL, et al.
Intravesical electromotive mitomycin C versus passive transport mitomycin C for high risk superficial bladder cancer: a prospective randomized study. J
Urol 2003;170:777–82; Şenyig˘it ZA, Karavana SY, lem-Özdemir D, et al. system for superficial bladder cancer: preparation of gemcitabine HCl-loaded
chitosan–thioglycolic acid nanoparticles and comparison of chitosan/poloxamer gels as carriers. Int J Nanomed 2015:10 6493–6507

32. Conclusion
• Gemcitabine is safe for intravesical administration @ 2gm/50ml
• Side effects incidence <20-25%, mostly grade I
• Efficacy for immediate post-op instillation for high grade doubtful
• Efficacy for primary Ta/1G3 inferior to BCG
• Efficacy for BCG refractory Ta/1G3 acceptable in short term
• Dosing schedule not clear – possibly weekly x 6 (+) monthly x 12
• Improvements in drug delivery are underway – already practiced in MMC

33. Thank you