Intravesical gemcitabine and marker lesion studies
A randomised, multicentre, open-label study was designed to evaluate the response rate of gemcitabine at three different doses levels in 32 patients with recurrent, multiple tumours (14 patients with TaG1 and 16 with TaG2) recruited from five Swedish centres . This was a marker lesion study, where a well-defined tumour was left in place after TUR and used to assess the effectiveness of gemcitabine. Generally patients with Ta NMIBC are considered at low to intermediate risk of progression and for this reason were the patient group chosen in case the treatment protocol was ineffective.
A central randomisation scheme was used to allocate patients to one of three schedules of intravesical gemcitabine, although there was no ‘blinding’ reported. Gemcitabine 2000 mg/100 mL saline was instilled for 60 min either as a single dose (11 patients), twice weekly for 3 weeks (11), or once per week for 6 weeks (10).
Of the 32 patients recruited, two were excluded because of protocol violations and none were lost to follow-up. This trial was designed as a feasibility study with 20 patients planned for each group; however, due to recruitment problems the trial was stopped early. This trial was assessed as low to intermediate risk of bias.
The results of this study indicated that a single dose of gemcitabine (2 g) induced a complete response in one of 11 patients (complete disappearance of the marker lesion with no new ones), no response in four of 11 patients and progressive tumour development in five of 11 patients. When gemcitabine was administered twice weekly for 3 weeks or once per week for 6 weeks, there were complete responses in four of 10 patients and four of 11 patients, respectively. There was no statistical analysis of these data but they suggest that a single dose is suboptimal and multiple doses are more effective. Eight of the 32 patients reported toxicity, mainly in the multiple dose groups consisting of nausea, anaemia, thrombocytopenia and fever.
As shown in Table 2[6,8,16–18], several published observation studies have reported tumour response data for marker lesions in patients with NMIBC. At a dose of 2 g gemcitabine given weekly for 6–8 weeks the response rates were between 14% and 69%. Disease progression was either not observed or low. Generally theses gemcitabine schedules were reported as well tolerated.
Table 2. Marker lesion studies of intravesical gemcitabine in NMIBC
|Study||Participants||Gemcitabine schedule||Study outcomes|
|Gontero et al. 2004 ||39 intermediate risk||2 g weekly × 6||CR: 56%|
|No progression in 17 NR.|
|No toxicity above grade 1.|
|De Berardinis et al. 2004 ||18 recurrent, multiple Ta–T1, G1–2||2 g weekly × 6||CR: 50% at 2 months|
|PR: 27%, NR: 22%. No progression observed.|
|Serretta et al. 2005 ||27 Ta–T1, 3 doses, 9 in each group||0.5 g, 1 g, and 2 g||CR: overall 23% (1 patient at 0.5g, 2 at 1g, 3 at 2g).|
|All weekly × 6||4 patients DF at 22 months|
|Calais da Silva and Calais da Silva 2005 ||42 multiple Ta–T1||2 g weekly × 8||CR: 69%|
|NR: 33%. No evidence of progression.|
|Haematuria in 2, dysuria in 4.|
|Brausi et al. 2007 ||14 primary, low-risk, single tumour <2 cm||2 g weekly × 6||CR: 2 (14%)|
|Failure: 11 (79%). 1 patient progressed (7%).|
|4 grade 1 and 1 grade 2 toxicity (pollakiuria)|
Single agent gemcitabine studies
A single postoperative instillation of gemcitabine was compared with a saline placebo in a multi-centre, double-blind, randomised study recruiting 355 patients with primary or recurrent Ta–T1 G1–3 TCC . The instillations of gemcitabine 2000 mg/100 mL saline were given between 30 and 40 min of TUR, followed by continuous saline irrigation for at least 20 h. Patients were stratified by primary or recurrent disease and centre. The primary endpoint was RFS with secondary objectives of type of recurrence, progression and adverse events. A second TUR with no instillation, and adjuvant BCG instillations were permissible. However, the method for randomisation was not stated and the number of patients lost before intravesical therapy was reported as 7.3% in the gemcitabine arm and 8.0% in the placebo arm. This trial was therefore considered at low risk of bias.
With follow-up cystoscopies at 3 and 6 months and then 6 monthly, an immediate instillation after TUR of gemcitabine was associated with a median RFS of 37.2 months compared with 40.2 months in the saline placebo arm (P= 0.78) . The RFS rates from a Kaplan–Meier analysis at 12 and 24 months were also similar for gemcitabine (77.7% and 64%) and placebo (75.3% and 60.7%). The overall recurrence rates were 35.5% and 36.3%, respectively. In a subgroup analysis, the RFS was not significantly associated with risk (high vs low), primary or recurrent disease, primary or secondary TUR, concomitant BCG therapy or the number of lesions. The number of patients who had disease progression was small in each group (gemcitabine three [2.4%], placebo one [0.8%]). In this study, there were fewer events than expected (87 recurrences and seven deaths) and the trial was stopped early. These data indicate that with this trial design, a single instillation of gemcitabine was no better than placebo for tumour recurrence.
Several observational studies [9,19–23] have evaluated the efficacy and tolerability of intravesical gemcitabine for NMIBC including immediate single-dose gemcitabine (Table 3). A dose of 2 g gemcitabine was consistently given but the dissolution volume, dwell time and frequency of administration varied. The treatment appears to be active with between 46% and 92% of patients diagnosed as recurrence-free after gemcitabine. Using these schedules gemcitabine was reported to be well tolerated with little or no toxicities above grade 1, which resulted in high patient compliance.
Table 3. Observational studies of gemcitabine in NMIBC
|Study||Participants||Gemcitabine schedule||Study outcomes|
|Buettner et al. 2004 ||23 with complete resection of NMIBC. Feasibility study.||2 g in 100 mL buffer for 30 min within 1 h of resection, then saline irrigation.||Nine tumour-free, one progression.|
|No toxicity exceeded grade 2.|
|Grade 1: bleeding – 1, haematuria – 1, dysuria – 4.|
|Grade 2: haematuria – 3, incontinence 1.|
|Iannelli et al. 2004 ||21 pTa–T1, G1–2. Multifocal in 19%.||2 g in 50 mL saline for 1 h weekly × 6 then monthly × 12.||Median follow-up 8.5 months.|
|Median DF interval 11.8 months.|
|Dysuria 48%, frequency 10%, haematuria 5%, nausea 5%.|
|De Cataldis et al. 2005 ||34 pTa–T1 G1–3||2 g in 50 mL saline for 2 h weekly × 6||CR: 89%|
|Side-effects did not exceed grade 1.|
|Bounedjar et al. 2005 ||60 (nine CIS, 51 pT1)||2 g in 100 mL saline weekly × 6||Follow-up 26 months. 92% recurrence-free, 8% relapsed.|
|Toxicities only grade 1: irritative bladder 5%, asthenia 3%, hot flashes 2%, nausea and vomiting 2%, anaemia 7%, leukopenia 5%.|
|Maffezzini et al. 2007 ||28 recurrent, low- or intermediate-risk NMIBC||2 g in 50 mL weekly × 4||CR: 46%|
|NR: 54%. Median (range) TTR 9.1 (2.9–26.5) months.|
|Local or systemic toxicities 26%.|
|Bartoletti et al. 2005 ||116 intermediate- or high-risk NMIBC||2 g weekly × 6||75% recurrence-free at 1 year|
|Urgency 14%, dizziness 5%, pain 1%, bladder ulcers 1%. 82% no toxicities.|
Intravesical gemcitabine compared with other intravesical agents
Several randomised trials have compared intravesical gemcitabine with either mitomycin C (MMC) or BCG. In a prospective, randomised trial Addeo et al. compared intravesical gemcitabine with MMC in 109 previously treated, recurrent patients who had progressed or failed BCG therapy. The schedules were gemcitabine 2000 mg/50 mL saline instilled for 1 h given weekly for 6 weeks (54 patients) or MMC 40 mg/50 mL instilled for 1 h within 2 days of TUR then weekly for 4 weeks (55). The ‘responders’ in each group had 10 monthly treatments. The primary endpoints of this study were disease-free interval (date of randomisation to first positive cytology), relative risk of tumour recurrence and the recurrence rate. Progression rates and toxicity were also assessed. Patients were stratified by age, stage (T1 or Ta) and grade (1–2 or 3) before randomisation to ensure these variables were equally distributed between patient groups. The method of randomisation was not reported, nor was there any blinding of treatment or outcome assessment. The 11 patients excluded from the initial 120 recruited were described as follows: ‘three not meeting the study inclusion criteria, four refused to participate and four for other reasons’. This study was considered low to intermediate risk of bias.
At a median follow-up of 36 months, the percentage of patients with tumour recurrence was 28% for gemcitabine and 39% for MMC (no P value given). The mean time to recurrence was longer for gemcitabine than MMC. The relative risk of recurrence (0.72 vs 0.94, P= 0.29) and the recurrence rate per 100 patient-months (1.26 vs 1.71, P= 0.31) were higher for the MMC group. The rate of disease progression by stage was also greater for MMC (11% vs 18%, P= 0.14). The overall incidence of adverse events was 38.8% for gemcitabine and 72.2% for MMC. These data suggest that intravesical gemcitabine has a more favourable efficacy and toxicity profile that MMC and may be potentially useful in BCG-refractory patients.
Three randomised trials compared the efficacy and tolerability of intravesical gemcitabine with intravesical BCG [11,14,15]. However, pooling of these data and meta-analysis was considered inappropriate because of considerable clinical heterogeneity.
An Egyptian randomised trial compared the efficacy and safety of gemcitabine with BCG and was presented in abstract form at the AUA meeting in 2011 . Between June 2006 and June 2008, this study randomised 80 patients with intermediate risk, primary Ta–T1 NMIBC without carcinoma in situ (CIS) to either agent.
All patients underwent complete TUR, after which they were randomised to six weekly instillations of either BCG 6 × 108 colony-forming units in 50 mL saline or 2000 mg gemcitabine in 50 mL saline. The main study endpoint was either completing a period of 18 months follow-up without relapse, or the appearance of recurrence or progression during the study period. All patients received the treatment to which they were randomised. However, they did not report the method used for the randomisation procedure. In addition, there was no ‘blinding’ of either the intervention received or outcome assessment. This study was reported as a meeting abstract and consequently was not subject to the same peer-review process as journal articles. For these reasons this study was categorised as having an intermediate risk of bias.
At a mean (sd, range) follow-up of 10.8 (2.7, 3–18) months, the percentage of patients with tumour recurrence was similar in each group (25% gemcitabine, 30% BCG, P= 0.61). The results were also similar when expressed according to Ta stage (22% gemcitabine, 26% BCG, P= 0.92) and T1 stage (27% gemcitabine, 33% BCG, P= 0.66). Overall progression rates were also similar between gemcitabine and BCG (P= 1.0), although no individual values were reported. When analysed according to stage, one patient in each group with Ta disease progressed, whilst those with T1 had a 9.1% progression rate for gemcitabine and 9.5% for BCG (P= 1.0). Dysuria was significantly more common in patients receiving BCG (12.5% vs 35%, P= 0.05) as was urinary frequency (10% vs 45%, P= 0.001). These data suggest that in patients at intermediate risk of recurrence or progression, gemcitabine appears equivalent to BCG but with less side-effects.
An Italian, single centre, prospective randomised trial compared intravesical BCG with gemcitabine in patients with high-risk NMIBC . Patients who had received prior chemotherapy within the previous 3 months or immunotherapy within 6 months were excluded. This study reported on the comparative rates for recurrence and disease progression, and tolerability for both BCG and gemcitabine. All patients underwent TUR, and then 4 weeks later a ‘second-look’ TUR was performed. Patients were randomised to either six weekly instillations of BCG 5 × 108 colony-forming units in 50 mL saline for 2 h (32 patients) or six weekly instillations of gemcitabine 2000 mg in 50 mL saline for 2 h (32). The maintenance therapy for patients that did not have recurrence in each group was at 3, 6, 12, 18, 24, 30 and 36 months. Randomisation was performed using a random number generator and permuted block design. There was no ‘blinding’ of the interventions or outcome assessments. In all, 10 patients were excluded after recruitment: eight did not meet the inclusion criteria and two refused to participate. This trial was rated as low to intermediate risk of bias.
At 3 months after TUR, all patients underwent cytology, cystoscopy and cold-cup biopsy. At a mean follow-up of 44 months the recurrence rate was significantly less with BCG (28.1% vs 53.1%, P= 0.037). The mean recurrence-free interval was also significantly longer with BCG (39.4 vs 25.6 months, P= 0.042). No patient in either group developed disease progression. There was no significant difference in local toxicity, e.g. cystitis (BCG 12.5%, Gemcitabine 9.3%) or systemic toxicity, e.g. fever (BCG 6.2%, Gemcitabine 0%). The results from this study suggested that gemcitabine was inferior to BCG in preventing or delaying tumour recurrence but that the favourable toxicity profile indicated that gemcitabine could be a treatment option for patients unsuitable for BCG therapy.
The third randomised trial comparing gemcitabine with BCG was a multicentre, prospective phase II study, recruiting 80 high-risk patients who were refractory to BCG therapy and had refused or were not suitable for cystectomy . The primary endpoint was the recurrence rate at 1 year with secondary endpoints of RFS, disease progression and toxicity. Patients were randomised to gemcitabine (40 patients), 2000 mg/50 mL for 6 weeks then weekly for 3 weeks at 3, 6 and 12 months or BCG (Connaught) 8 mg/50 mL (same schedule as gemcitabine; 40 patients). Both treatments were started 4–6 weeks after the last TUR. A central computer randomisation method was used to allocate treatment options. This was an open-label study, so there was no ‘blinding’ of treatments or outcomes. In all, 12 patients were excluded from the 92 recruited patients and the reasons documented were: eight not meeting the inclusion criteria, three refused to participate and one for other reasons. This trial was assessed as low risk of bias.
BCG-refractory, high-risk patients had a recurrence rate of 52.5% (21/40) after intravesical gemcitabine compared with 87.5% (35/40) for intravesical BCG. This difference was statistically different (P= 0.002). The recurrence rates at 2 years extrapolated from the Kaplan–Meier analysis, confirmed the significant difference (19% gemcitabine, 3% BCG; hazard ratio 0.15, 95% CI 0.1–0.3, P < 0.008). However, there was no significant difference in the RFS (hazard ratio1.1, 95% CI 0.8–1.2, P= 0.9). Progression rates were also similar between groups: gemcitabine 33% and BCG 37.5% (P= 0.12). It appears that intravesical gemcitabine is significantly more active than BCG in reducing and delaying tumour recurrence in patients who have failed prior BCG therapy. Gemcitabine may therefore be an effective option as a second-line treatment for this difficult group of patients where cystectomy is refused or not suitable.