Bladder Cancer Clinical Trial
Official title:
Sequential Bacillus Calmette-Guérin and Electromotive Mitomycin-C Versus Bacillus Calmette-Guérin Alone for High Risk Superficial Bladder Cancer: a Prospective Randomised Study
Intravesical treatment for superficial bladder cancer has been used for the past 4-5
decades. Intravesical chemotherapy is beneficial in terms of recurrence and time to
recurrence in grade 1-2 stage Ta tumours, usually non-invasive. Intravesical chemotherapy
has negligible effect on disease progression in high-risk superficial bladder cancer—ie,
grade 3, stage T1, and carcinoma in situ. However, BCG as induction and maintenance
treatment effectively delays progression. Electromotive mitomycin increases tissue uptake
compared with that of passive diffusion. Electromotive mitomycin has emerged as an
alternative or complementary treatment to BCG. The rationale for combining anticancer drugs
is based on the need to increase efficacy and reduce emergence of resistant malignant cells.
This approach is not frequently applied to use of intravesical agents for treatment of
superficial bladder cancer, for which immunotherapeutic BCG and chemotherapeutic mitomycin
seem to be a potentially effective combination. Studies have addressed concurrent use of
mitomycin and BCG, and assigned two roles to mitomycin: antitumor action and
tissue-scarifying (ie, surface-modifying) effect that enables BCG to attach more efficiently
to the urothelium. The investigators therefore aimed to assess whether induction of
inflammation by use of BCG before mitomycin treatment makes the bladder mucosa more
permeable and thus enables mitomycin to reach the target more easily. This randomised trial
to compare the efficacy of sequential BCG and electromotive mitomycin with that of the
current standard of BCG alone for patients with high-risk superficial bladder cancer.
After transurethral resection and multiple biopsies patients with stage pT1 bladder cancer
are randomly assigned to: 81 mg BCG infused over 120 min once a week for 6 weeks; or to 81
mg BCG infused over 120 min once a week for 2 weeks, followed by 40 mg electromotive
mitomycin (intravesical electric current 20 mA for 30 min) once a week as one cycle for
three cycles (n=107). Complete responders underwent maintenance treatment: those assigned
BCG alone had one infusion of 81 mg BCG once a month for 10 months, and those assigned BCG
and mitomycin had 40 mg electromotive mitomycin once a month for 2 months, followed by 81 mg
BCG once a month as one cycle for three cycles. The primary endpoint was disease-free
interval; secondary endpoints were time to progression; overall survival; and
disease-specific survival. Analyses were intention to treat.
All patients with histologically proven stage pT1 urothelial carcinoma of the bladder,
whether papillary or solid, are regarded as being at high risk for tumour recurrence and at
moderate to high risk for progression because of: multifocal pT1, primary or recurrent,
grade 2 transitional-cell carcinoma; primary or recurrent pT1, multifocal or solitary, grade
3 transitional-cell carcinoma; or pT1 with carcinoma in situ. Inclusion criteria are: age 18
years or older; adequate bone-marrow reserve; normal renal function; normal liver function;
and Karnofsky performance status between 50 and 100. Exclusion criteria are: previous
treatment with BCG or electromotive mitomycin; treatment with any other intravesical
cytostatic agent within the past 6 months; concomitant urothelial tumours of the upper
urinary tract; previous muscle-invasive (ie, stage T2 or higher) transitional-cell carcinoma
of the bladder; bladder capacity less than 2 L; untreated urinary-tract infection; severe
systemic infection (ie, sepsis); urethral strictures that would prevent endoscopic
procedures and repeated catheterisation; disease of upper urinary tract (eg, vesicoureteral
reflux or urinary-tract stones) that would make multiple transurethral procedures a risk;
previous radiotherapy to the pelvis; other concurrent chemotherapy; treatment with
radiotherapy-response or biological-response modifiers; history of tuberculosis; other
malignant diseases within 5 years of trial registration (except for basal-cell carcinoma);
pregnancy or nursing; and psychological, familial, sociological, or geographical factors
that would preclude study participation.
Study design The institutional review boards of every participating centre approved the
study design. Every patient enrolled signed an informed-consent form approved by the
institutional review boards. All patients underwent: urinary cytology of the bladder and
upper urinary tract; random cold-cup biopsies of the bladder and prostatic urethra—ie,
sampling of seemingly healthy urothelium and of suspicious areas; and complete transurethral
resection of all bladder tumour visible on endoscopy, ensuring muscle is included in
resected samples. Patients with positive or suspect cytology, carcinoma in situ, multifocal
tumours, or grade 3 tumours underwent restaging transurethral resection 4-5 weeks later. All
clinical assessors are adequately trained in the above procedures, and no methods are used
to enhance the quality of measurements. All biopsy samples of tumour and bladder are
reviewed by a pathologist for stage and grade. Tumour stage is classified according to the
1997 TNM classification of the International Union Against Cancer, and tumour grade is
defined in accordance with the 1973 WHO classification. Patients are randomised within 10
days of the first or restaging transurethral resection. Randomisation and data collection
are done by use of a central computer. Patients are allocated to BCG alone or to BCG and
electromotive mitomycin by use stratified, blocked randomisation cross 14 strata as a result
of four factors: primary versus recurrent tumours; multifocal versus unifocal tumours; grade
3 versus grade 2 tumours; and presence versus absence of carcinoma in situ. MV generated and
coordinated the randomisation process. This study is not blinded because of differences in
treatment schedules and drug appearance.
Treatment schedules All patients are scheduled to receive their allocated intervention about
3 weeks after transurethral resection and multiple, random biopsy sampling. The BCG
instillation consisted of 81 mg wet weight BCG Connaught substrain (ImmuCyst®, Alfa
Wassermann SpA, Bologna, Italy). Lyophilised (ie, freeze-dried) BCG is suspended in 50 mL
bacteriostatic-free solution of 0·9% sodium chloride. After draining of the bladder, the
suspension is infused intravesically through a Foley catheter. The solution is retained in
the bladder for 120 min, followed by emptying of the bladder and removal of the catheter.
Patients randomly allocated to BCG and mitomycin, are placed on fluid restriction and 2 g
ingested sodium bicarbonate the night before treatment, the morning of treatment, and 2 h
before treatment with mitomycin. A Foley catheter is inserted and postvoid residual volume
is reduced to less than 10mL. 40 mg mitomycin (Mitomycin, Kyowa Italiana Farmaceutici, Srl,
Milan, Italy) dissolved in 100 mL water is infused intravesically through the Foley catheter
by gravity and retained in the bladder for 30 min, while 40-60 mA per s to a maximum of 20
mA or 30 min pulsed electric current is given externally.13 Two dispersive cathode
electrodes are placed on lower abdominal skin that had been degreased with alcohol and a
2-5-mm layer of conductive gel applied. The bladder is then emptied and the catheter
removed. The BCG-alone group is assigned one course of intravesical treatment per week for 6
weeks; patients assigned sequential BCG and electromotive mitomycin are assigned one course
of treatment per week for 9 weeks, for whom one cycle consisted of two BCG infusions and one
mitomycin infusion (three cycles in total). Patients in the BCG-alone group who are
disease-free 3 months after treatment are scheduled to receive monthly infusions of BCG for
10 months. Patients in the BCG-and-mitomycin group who are disease-free 3 months after
treatment are scheduled to receive one infusion a month for 9 months: three cycles of
mitomycin, mitomycin, and BCG (ie, six infusions of mitomycin and three infusions of BCG.
Maintenance treatment for both groups is given to the same dose and methods of infusion as
initial allocated treatment.
Role of the funding source The sponsor of the study has no role in study design; in the
collection, analysis, or interpretation of data; or in the writing of the report.
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Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
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