ELECTROMOTIVE DRUG ADMINISTRATION (EMDA)
by PHYSIONIZER MINI 30N2
EMDA – ElectroMotive Drug Administration is Imported in Thailand by Siam Trade development as License Holder of Physion SRL, Italy. Below its background and efficacy studies.
1. PREMISE AND METHODOLOGY
PHYSIONIZER MINI 30N2 is a device used as carrier of drugs (commonly Mitomycin C) into the urothelium of the bladder affected by cancer.
PHYSION Srl, Italian Company, created the device Physionizer 30 (now called Physionizer Mini 30N2) in early 1990’s as drug administration vehicle for bladder cancer treatments. Principle is the enhancement of effects of Mitomycin C (MMC) and Bacillus Calmette-Guerin (BCG) in the treatment of high-risk non muscle-invasive bladder cancer through electrophoresis (EMDA)
Scope of the present file is to prove that the device Physionizer Mini 30N2 , used as vehicle for ElectroMotive Drug Administration, is
- effective as treatment;
- Safe for the patient;
- Cost effective for the hospital.
In order to do this, we selected the main articles from the huge literature about the method (EMDA) performed by our device (Physionizer Mini 30N2).
We start back from 1996, when tests were performed on animals; then comparisons between BCG passive administration and through Physionizer Mini 30N2; then, results on large scale of treatments in different periods (2008, 2003, 2006, 2013, and latest dated 2018).
Scope of this summary is to show that the device Physionizer Mini 30N2 as vehicle for EMDA is safe and effective both in terms of benefice for the patient and in terms of costs for the hospital.
2. BACKGROUND
Bladder cancer is the 7th most common cancer worldwide.
Most bladder tumors (75-80 %) are non-muscle invasive cancer (Stage Ta, T1 and Tis).
Incidence rate are consistently lower in women than men, although sex differences varied greatly between countries.
There were almost 500.000 new cases in 2018.
The key challenge is to prevent recurrence and disease progression.
Physionizer Mini 30N2 has been designed to support doctors in this prevention by enhancing the effect of MMC and BCG treatments in the patients.
3. PHYSIONIZER MINI 30N2 AND ELECTROMOTIVE DRUG ADMINISTRATION (EMDA)
Physionizer Mini 30N2 is a device that enables the Electromotive drug administration (EMDA), a non-invasive method of enhancing local drug penetration across the urothelium of the bladder.
Physionizer Mini 30N2 can be used for EMDA either prior to or after TURBT.
The purpose of Physionizer Mini 30N2 is to augment the effect of intravesical chemotherapy by creating an electric field across the bladder wall which increase urothelium’s permeability.
Physionizer Mini 30N2 is composed by 3 parts: a current generator, a catheter with an electrode inside, and two electrodes to apply externally to the apparatus.
Internal (catheter) and external electrodes create, when the current is emitted by the generator, an electric field that stimulates directional ionic and solute movement of intravesical fluid: drug is delivered to a greater tissue depth and results in greater concentration than is possible with passive diffusion.
Physionizer Mini 30N2 allows the operator to control the rate of drug administration, by varying the current intensity.
The applied electric current causes no biological damage to tissue and no chemical modification of drug.
3.1. PROCEDURE
The procedure can be conducted on an outpatient basis. With the patient in a supine position electrodes are placed on the skin of the lower abdominal wall, an intravesical electrode contained in a specially designed catheter is then inserted into the bladder through the urethra, using an anesthetic gel as lubricant. A chemotherapeutic drug solution, usually mitomycin C (MMM-C) in bidistilled water, is instilled intravesical into the bladder through the catheter, as in standard intravesical chemotherapy.
The cutaneous and intravesical electrodes are connected to a generator that creates an electric field. Treatment last for 20 minutes. After the procedure the bladder is drained and the catheter is removed.
Physionizer Mini 30N2 scheme – Source: Di Stasi SM., Riedl C., “updates in intravesical electromotive druig administration of mitomycin-C for non-muscle invasive bladder cancer – World Journal of Urology, Feb 21st, 2009.
3.2. PHARMACODINAMICS AND PHARMODYNAMICS
Mechanism of transport with Electromotive drug administration (EMDA) to the urinary bladder(1) (2)
Anesthetized adult mongrel dogs were studied(1). An intravesical anode was inserted through a Foley catheter into the urinary bladder. Two patch electrodes were positioned on the animals’ abdominal skin. Both skin and intravesical electrodes were attached to a direct current generator (Physionizer Mini 30N2). The bladder was then distended with an anionic blue dye (methylene blue). 15 mA pulsed direct current was applied for 40 minutes. After EMDA, the bladder was surgically removed and representative sections of full thickness bladder wall were immediately frozen in liquid nitrogen. Methylene blue was used to visually demonstrate Physionizer-enhanced anion penetration into bladder submucosa and muscularis.
This experimental model demonstrates significant submucosal and muscolaris methylene blue penetration in the presence of an electric field.
Same results were achieved with MMC-C in humans (2).
Physionizer Mini 30N2 significantly increases MMC-C concentration in all of the layers of the bladder wall (urothelium, lamina propria and superficial muscle layers): MMC-C concentration is 5-7 times increased compared to Passive Diffusion (PD); plasma levels remain well below toxic concentration.
Data above are expressed as µg of MMC/g of wet tissue, the means ± 1 SE of 14 experiments per group.*,p < 0.0005 and **, p < 0.0001 versus PD)
4. EVIDENCE-BASED TREATMENT
4.1. Efficacy
Many authors have published studies about Electromotive Drug Administration for non muscle invasive bladder cancer (3) (4) (5) (6) (7) (8) (9) (10) (11) (12) (13) (14) (15) (16)
Different clinical protocols have been studied to evaluate the impact of EMDA/MMC-C and compare the different modalities of treatment with EMDA/MMC-C. Most studied protocols have been performed with Physionizer Mini 30N2, others with devices with same specifications/functions.
| SUMMARY REPORT | |||
| Pubblications | Type of trial | Patients | Tumors |
| Di Stasi 2003 (3) | RCT | 108 | pTis, pTis +pT1 |
| Di Stasi 2006 (4) | RCT | 212 | pT1 and pTis; high risk |
| O’Brien (5) | RCT | 151 | High grade Ta/T1 (48%)
High grade Ta/T1 + Cis (32%) Primary Cis (18%) Recurrent large Volume low grade Ta (2%) |
| Di Stasi 2011 (6) | RCT | 374 | pTa and pT1; intermediate and high-risk |
| Brausi 1998 (7) | non-RCT | 28 | pTa and pT1 |
| Riedl 1998 (8) | Case series | 22 | pTa, pT1 and pTis |
| Colombo 2001(9) | Non-RCT | 80 | pTa and pT1 |
| Di Stasi 2012 (10) | RCT | 212 | pT1 |
| Canada 2018 (13) | 30 | pTa, pT1 and pTis | |
| Gemelli,Roma (14) | 26 | TaG3 (15,4%), T1G3 (53,8%), Tis (15,4%), TaT1G3+Tis (15,4 %) | |
| Policlinico Bari, 2018 (15) | 87 | High risk | |
| Total cases under consideration | 1330 | ||
4.1.1. Di Stasi SM, Stephen RL et al. Intravesical electromotive mitomycin C versus passive transport mitomycin C for high risk superficial bladder cancer :a prospective randomized study vs BCG – Journal of Urology 2003; 170 (3):777-782.(3)
| Patients | Primary endpoint | Efficacy Resuts |
| 108 patients with histologically proven multifocal carcinoma in situ (Tis) of the bladder (most had concurrent pT1 papillary transitional cell carcinoma) were randomly assigned to:
81 mg BCG (n=36); or 40 mg electromotive mitomycin (intravesical electric current 20 mA for 30 min) (n=36), or 40 mg passive transport mitomycin (n=36). Patients in the 3 groups who had a complete response to the initial 6 weekly treatments underwent a further 10 monthly instillations. If cancer persisted at 3 months, a second 6 week course was given. If disease persisted at 6 months, there was a crossover to a 6-week second line course of BCG for patients in the 2 MMC groups and electromotive MMC for patients in the BCG group |
The primary study end point was a complete response at 3 and 6 months following treatment.
The aim was to evaluate differences between responses to passive MMC, estimated at 33%, and to electromotive MMC, anticipated to be equivalent to that of a BCG response rate of 70%. |
The complete response for
electromotive vs passive MMC at 3 and 6 months was 53% versus 28% (p < 0.036) and 98% versus 31% (p < 0.012). For BCG the responses were 56% and 64%. Median time to recurrence was 35 vs 19.5 months (p < 0.013) and for BCG it was 26 months. |
RESULT:
EMDA increases bladder uptake of MMC, resulting in an improved response rate and an improved median time to recurrence
| MMC | EMDA MMC | BCG | |
| No. OF CASES | 36 | 36 | 36 |
| COMPLETE RESPONSE AT 3 MONTHS | 28% | 53% | 56% |
| COMPLETE RESPONSE AT 6 MONTHS | 31% | 58% | 64% |
| TIME TO RECURRENCE ( months ) | 19,5 | 35 | 26 |
4.1.2 Sequential BCG and electromotive mitomycin versus BCG alone fopr high-risk superficial bladder cancer: a randomized controlled trial – The Lancet Oncology 2006; 7 (1):43-51- SM Di Stasi UnIversity Tor Vergata, Rome, Italy (4)
| Patients | Primary endpoint | Efficay Results |
| 212 patients with stage pT1 bladder cancer were randomly assigned to:
81 mg BCG infused over 120 min once a week for 6 weeks (n=105); 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 c) those assigned BCG alone had one infusion of BCG once/month for 10 months, d) 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
either disease-free survival in patients without carcinoma in situ or period from randomisation to first recurrencenoted by cystoscopy in patients with TCC |
At a mean follow-up of 88 months 58% (62/107) of the patients in the BCG plus EMDA chemotherapy group were found to be _ disease-free compared with 42% (44/105) patients in the BCG alone group (p = 0.0012).
Patients in the BCG plus EMDA chemotherapy group had a lower overall mortality (22%; 23/107) (95% CI 13.5 to 29.5) compared with patients in the BCG alone group (32%; 34/105) (95% CI 23.4 to 41.4) at a mean follow-up of 88 months Hazard ratio 0.586 (p = 0.045). |
RESULT:
Patients in sequential BCG-EMDA MMC group have a higher disease free interval (69 months ) and a lower recurrence than patients in BCG alone group ( 21 months )
| BCG | BCG- EMDA MMC | DIFFERENCE | |
| NO OF CASES | 105 | 107 | 2 |
| DISEASE FREE INTERVAL (months) | 21 (15-54) | 69 (55-86) | 48 |
| RATE OF RECURRENCE | 57,9% | 41,9% | 16% |
| PROGRESSION | 21,9% | 9,3% | 12,6% |
| OVERALL MORTALITY | 32,4% | 21,5% | 10,9% |
4.1.3 Sequential bacillus Calmette-Guerin/Electromotive Drug Administration of Mitomycin C as the Standard Intravesical Regimen in high-risk non muscle invasive bladder cancer: 2-year Outcomes – Journal of Urology Vol.195, 1697-1703 June 2016 – Christine Gan, Tim O’Brien Guy’s and St. Thomas’ National Health Service Trust, London, UK (5)
| Patients | Primary endpoint | Efficay Results |
| Of the 151 patients with high risk, non-muscle invasive bladder cancer treated between June 2009 and 2013, 44 underwent primary cystectomy and 107 received sequential bacillus Calmette-Guerin/electromotive drug administration of mitomycin C.
Disease was high grade Ta/T1 in 86 patients (80%), of whom 34 (32%) also had carcinoma in situ. A total of 19 patients (18%) had primary carcinoma in situ and 2 had recurrent large volume, low grade disease. |
Primary outcomes were the recurrence rate at first, 1-year and 2-year cystoscopy.
Results were analyzed by intent to treat and by the actual treatment received. |
Of the 107 patients receiving sequential bacillus Calmette-Guerin/EMDA of mitomycin C. 104 underwent first check cystoscopy, including 90 (87%) who were clear. Of the 90 complete responders 86 underwent 1-year cystoscopy, including 74 (86%) who were recurrence-free. Of these 74 patients, 71 underwent 2-year cystoscopy, of whom 66 (93%) remained recurrence-free. |
RESULT:
This study confirms the excellent oncology efficacy of sequential BCG/Electromotive Drug Administration of MMC-C in cases of high-risk non muscle invasive bladder cancer
4.1.4 Electromotive instillation of mitomycin immediately before transurethral resection for patients with primary urothelium non-muscle invasive bladder cancer: a randomised controlled trial – The Lancet Oncology Vol 12 September 2011 – Savino Mauro Di Stasi University of Rome Tor Vergata, Italy (6)
| Patients | Primary endpoint | Efficay Results |
| 124 patients were randomly assigned to receive TURBT alone,
126 to receive immediate post-TURBT PD Mitomycin C, -and 124 to receive immediate pre-TURBT EMDA mitomycin C. Eligible participants had histologically proven primary pTa and pT1 urothelial carcinoma of the bladder. |
The primary endpoint were:
recurrence rate disease-free interval for patients who were disease-free after treatment-ie, time from randomization to the first cystoscopy noting recurrence. |
Patients assigned to receive EMDA mitomycin before TURBT had a lower rate of recurrence (44 [38%] of 117) than those assigned to receive PD mitomycin after TURBT (70 [59%] of 119) and TURBT alone (74 [64%] of 116; log-rank p<0-0001).
Patients assigned to receive EMDA mitomycin before TURBT also had a higher disease-free interval (52 months, IQR 32-184) than those assigned to receive PD mitomycin after TURBT (16 months, 12-168) and TURBT alone (12 months, 12-37; log rank p<0.0001) |
RESULT:
Intravesical EMDA-MMC pre-Turbt reduces recurrence rates and enhances the disease free interval ( compared with intravesical MMC passive diffusion post-Turbt and Turbt alone ): exfoliated tumor cells that could implant were killed.
Patients in EMDA-MMC pre-Turbt group have an higher disease free interval (52 months ) and a lower time to recurrence ( 38 %)
| TURBT | DP MMC POST-TURBT | EMDA MMC PRE-TURBT | |
| NO. OF CASES | 124 | 126 | 124 |
| DISEASE FREE INTERVAL (months ) | 12 (12-37) | 16 (12-168) | 52 (32-184) |
| RATE OF RECURRENCE | 64 % (74/116) | 59 % (70/119) | 38 % (44/117) |
4.1.5 Intravesical sequential bacillus Calmette-Guérin and electromotive mitomycin versus bacillus Calmette-Guérin alone for stage pT1 urothelium bladder cancer – AUA annual meeting 2012, abstract 1670.22-5-2012 – Savino Mauro Di Stasi (10)
Is Intravesical BCG alone still the only truly effective intravesical therapy for non-muscle invasive bladder cancer ? – Journal of Urology Vol.193, No. 4S, Supplement, Saturday, May 16, 2015 – Savino Mauro Di Stasi
|
121-month follow up of the 212 patients included in the study “ Sequential BCG and electromotive mitomycin versus BCG alone for high-risk superficial bladder cancer: a randomises controlled trial – The Lancet Oncology 2006 “ (3)
|
RESULT:
Patients assigned to BCG-EMDA MMC group have a higher disease free interval and a lower recurrence than patient in BCG alone group: in patients with pT1 NMIBC, BCG-EMDA MMC provided better results than BCG alone
| 121 months Follow-up | BCG – EMDA MMC | BCG |
| DISEASE FREE INTERVAL (months) | 79 | 26 |
| RATE OF RECURRENCE | 45% | 62% |
| OVERALL MORTALITY | 44% | 59% |
4.1.6 Intravesical sequential BCG/Electromotive drug administration Mitomycin C ( EMDA-MMC ) in high risk non muscle invasive bladder cancer- results from a retrospective analysis- Di Modugno et al., Policlinico di Bari Urologia II, Italy (15)
| Patients | Primary endpoint | Efficay Results |
| This study confirms the efficacy of sequential administration of intravesical BCG and EMDA-MMC in terms of clinical response, complication rate and patients’ compliance | 87 patients with high-risk non muscle invasive bladder cancer
Follow-up 43 months |
Disease recurrence was found in 17/87 patients (19,5%)
Only 2/87 patients had a disease progression (2,3%) |
4.1.7 Sequential administration of BCG and electromotive drug administaration ( EMDA ) of mitomycin C ( MMC ) in non muscle invasive bladder cancer having previosly recieved intravesical therapy – Journal of Oncology Vol.199, No.4S, Supplement, Monday, May 21, 2018 – Tristan Juvet et al. Princess Margaret Hospital Cancer Center, Toronto, Canada (13)
Two studies on high-risk “ BCG failure “ NMIBC
| Patients | Primary endpoint | Efficay Results |
| 30 patients (CIS, pT1, pTa ) who had received an initial BCG traitment and progressed, received BCG- EMDA MMC traitment | Determinate the efficacy of EMDA MMC in patients having failed treatment with BCG | Following BCG- EMDA MMC traitment progression-free survival rates were 79,5% at 1 year and 61,7% at 2 years from the date of BCG-EMDA MMC induction |
| AT 1 YEAR | AT 2 YEARS | |
| PROGRESSION FREE RATE | 79,5% | 61,7% |
4.1.8 Electromotive Drug administration ( EMDA) of mitomicyn C as first line salvage therapy in high risk “ BCG-failure “ non muscle invasive bladder cancer: 3 years follow-up outcomes”- BMC Cancer December 6, 2018 – Marco Racioppi et al. – Policlinico Gemelli, Rome, Italy (14)
| Patients | Primary endpoint | Efficay Results |
| 26 patients with high grade NMIBC unresponsive after at one cycle of intravesical immunotherapy with BCG.
Patients received 6 weekly instillation of MMC (40 mg) and then a monthly treatment for a total of 6 treatments. |
Determinate the efficacy ( in terms of recurrence and progression ) of EMDA MMC in patients having failed treatment with BCG | After 3 years of follow-up, 16 patients (56,5% ) preserved their bladder, 10 patients (43,5% ) underwent radical cistectomy.
Disease-free rates at 3 years follow-up were: 75% (TaG3), 71,4% (T1G3 ), 50% (Cis)and 25% TaT1G3+Cis ) |
RESULT:
The EMDA MMC traitment is an efficay tool in the long term conservative treatment of the high-risk non-muscle invasive bladder cancer unresponsive to BCG
4.1.8 Intravesical electromotive administration of drugs for treatment of superficial bladder cancer: a comparative phase II study- Urology 1998 Mar; 51(3): 506-9 – M. Brausi, Ramazzini Hospital Center, Carpi , Modena, Italy (7)
| Patients | Primary endpoint | Efficay Results |
| 28 patients with multifocal Ta-T1, G1-G2, primary or recurrent NMIBC
-13 were assigned to receive 40 mg mitomycin C once a week for 8 weeks (group A) -15 were treated with EMDA-MMC C once a week for 8 weeks All lesions in the bladder were previously resected except one (marker) Marker lesion diameter: 0,4-1,5 cm |
Evaluete the efficacy of electromotive drug adminitration ( EMDA ) of mitomycin-C | Group A
Complet responder * ( CR ): 42% In responder patients recurrence rate was 60% and disease free interval was 10.5 months
Group B: CR *: 40% In responder patients recurrence rate was 33% and and disease free interval was 14.5 months |
*Complete responder: patients who demonstrate complete macroscopic and histological disappereance of the marker lesion with negative cytology (CR)
| Group A | Group B | |
| RECURRENCE RATE | 60% | 33% |
| DISEASE FREE INTERVAL (months) | 10.5 | 14.5 |
RESULT:
Patients in EMDA-MMC group have a longer disease free interval and a lower recurrence rate
5. SAFETY
In different studies, the groups did not differ in the frequency or severity of side effects.
For examples, the tables below display the percentage of side effects in the study published in the Journal of Urology 2003(3) and in the Lancet Oncology 2006 (4)
| Journal of Urology 2003; 170 (3): 777-782 | BCG (%)
(n=36) |
Electromotive MMC (%) (n=36) | Passive MMC (%) (n=36) |
| Urinary frequency
Bacterial cystitis Drug induced cystitis Visible hematuria Prostatitis Epididymitis Fever General malaise Fatigue Allergic reactions |
21 (58.3%)
9 (25.0%) 24 (66.7%) 26 (72.2%) 1 (2.8%) 1 (2.8%) 7 (19.4%) 11 (30.5%) 16 (44.4%) – |
7 (19.4%)
7 (19.4%) 13 (36.1%) 8 (22.2%)
1 (2.3%) 3 (8.3%) |
6 (16.7%)
7 (19.4%) 9 (25.0%) 6 (16.7%)
1 (2.8%)
2 (5.6%) |
Local and systemic side effects are significantly more prominent in the BCG arm than in EMDA MMC arm.
| LANCET Oncology 2006; 7(4):43-51 | BCG (%) (n=105) | Seq BCG and EMDA mitomycin C (%) (n=107) |
| Dysuria
Bacterial cystitis Drug-induced cystitis Macroscopic haematuria Prostatitis Protatitis Fever Influenza-like symptoms Fatigue |
51 (48.5%)
14 (13.3%) 46 (43.8%) 61 (58.1%) 1 (1.0%) 24 (22.8%) 34 (32.4%) 32 (30.5%) |
54 (50.5%)
16 (14.9%) 49 (45.8%) 64 (59.8%) 0 21 (19.6%) 33 (30.8%) 32 (29.9%) |
Toxic effects associated with sequential BCG-EMDA MMC are no worse than those associated with BCG alone and were mainly localized to the bladder.
Two recent studies (2018) evaluated the safety of EMDA treatment
- “Electromotive Drug administration (EMDA) of mitomicyn C as first line salvage therapy in high risk “ BCG-failure “ non muscle invasive bladder cancer: 3 years follow-up outcomes”- BMC Cancer December 6, 2018 – Marco Racioppi et al. – Policlinico Gemelli, Rome, Italy(14)“
“toxicity was acceptable […] and it was not so different from data reported in the literature“, in fact “ we reported lower rates than those reported” by other authors.
| Systemic, n° of patients (%) | 3 (11.5%) |
| Local, n° of patients (%) | 6 (23.1%) |
| Pain | 3 (11.5%) |
| Bladder spasm | 3 (11.59%) |
| Dysuria | 5 (15.4%) |
| Hematuria | 1 (3.8%) |
| Difficult catheter insertion | 1 (3.8%) |
| Frequency/urgency | 3 (11.5%) |
| Nocturia | 2 (7.7%) |
- “Intravesical sequential BCG/ Electromotive drug administration Mitomicyn C (EMDA MMC ) in high risk non muscle invasive bladder cancer- results from a retrospective analysis – Di Modugno et al. Policlinico Bari, Urologia II, Bari, Italy“ (15)
“Intravesical sequential BCG- EMDA MMC is well tolerated”
| 9/87 (10,3%) | patients showed side effects: |
| 4/9 (44,4%) | recurrent urinary tract |
| 2/9 (22,3%) | severe lower tract symptoms |
| 1/9 (11,1%) | urethorrhage |
| 1/9 (11,1%) | haematuria |
RESULT:
EMDA dispensed by Physionizer Mini 30N2 is a safe and well tolerated technology
6. CONCLUSION
The Studies discussed above evidenced 3 different modalities of EMDA treatment with Physionizer Mini 30N2
- EMDA/MMC-C instillation with Physionizer Mini 30N2 in intermediate-risk(7) and high-risk(3) non muscle-invasive bladder cancer and for BCG failure patients(14)
- Sequential BCG – EMDA/MMC treatment through Physionizer Mini 30N2 for high-risk non muscle-invasive bladder cancer(4),(5),(10) and for BCG failure patients(13),(15)
- Pre-TURBT instillation of EMDA/MMC through Physionizer Mini 30N2 for intermediate-risk and high-risk non muscle invasive bladder cancer(6)
The results of these studies in intermediate and high risk NMIBC patients treated with Physionizer Mini 30N2, show significant short and long-term benefits with median disease-free interval longer and lower rate of recurrence.
An appropriate patients follow-up was done during two to twelve years post treatment administration.
Physionizer Mini 30N2 and EMDA treatment reduce medium term and long term costs (less cystectomies, less cystoscopies) and improve patients’ quality of life.
In addition, the 10-year cost-effectiveness randomized study(16) comparing sequential treatments with BCG/EMDA MMC-C instilled by Physionizer Mini 30N2 versus BCG alone, shows that the sequential therapy is a cost-effective treatment for patients with high risk non muscle invasive bladder cancer.
7. REFERENCES
1) Gurpinar T, Truong LD, Wong HY, Griffith DP Electromotive drug administration to the urinary bladder: an animal model and preliminary results – Journal of Urology, Vol.156, No.4,01.10.1996,p.1496-1501
2) Di Stasi SM, Stephen RL Electromotive versus Passive Diffusion of Mitomycin C into human bladder wall – Cancer research October 1999 Vol 59, Issue 19
3) 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 vs BCG – Journal of Urology 2003; (3):777-782.
4) Di Stasi SM, Giannantoni A,Giuroli A et al Sequential BCG and electromotive mitomycin versus BCG alone for high-risk superficial bladder cancer: a randomised controlled trial – The Lancet Oncology 2006; 7(1):43-51
5) Christine Gan, Tim O’Brien Guy’s Sequential bacillus Calmette-Guerin/Electromotive Drug Administration of Mitomycin C as the Standard Intravesical Regimen in high-risk non muscle invasive bladder cancer: 2-year Outcomes – Journal of Urology Vol.195, 1697-1703 June 2016 –
6) Di Stasi SM, Valenti M, Verri C et all Electromotive instillation of mitomycin immediately before transurethral resection for patients with primary urothelium non-muscle invasive bladder cancer: a randomised controlled trial – The Lancet Oncology Vol 12 September 2011;12(9):871-879
7) M.Brausi, B.Campo, G.Pizzocaro et al Intravesical electromotive administration of drugs for treatment of superficial bladder cancer: a comparative phase II study – Urology 1998 Mar; 51(3): 506-9
8) Riedl CR, Knoll M, Plas E, Pfluger H Intravesical electromotive drug administration technique: preliminary results and side effects. J Urol 1998;159 (6) 1851-1856
9) Colombo R, Brausi M et al Thermo-chemotherapy and electromotive drug administration of mitomycin C in superficial bladder cancer eradication, a pilot study on marker lesion. Eur Urol 2001; 39(1):95-100
10) Di Stasi SM, Verri C, Liberati E et al Intravesical sequential bacillus Calmette-Guérin and electromotive mitomycin versus bacillus Calmette-Guérin alone for stage pT1 urothelium bladder cancer – AUA annual meeting 2012, abstract 1670.22-5-2012
11) Oosterlinck W, Chemotherapy: Electromotive mitomycin in superficial bladder cancer. Nat Rev Clin Oncol 2011; 8(11): 633-634
12) Bassel G Bachir, Wassim Kassouf- Contempory cost-effectiveness analysis comparing sequential bacillus Calmette- Guerin and electromotive mitomycin versus bacillus calmette- Guerin alone for patients with high-risk non-muscle-invasive bladder cancer- Cancer 2014; 120:2424-2431
13) Juvet T, Wallis C, Krimus L et al.Sequential administration of BCG and electromotive drug administaration ( EMDA ) of mitomycin C ( MMC ) in non muscle invasive bladder cancer having previosly recieved intravesical therapy – Journal of Oncology Vol.199, No.4S, Supplement, Monday, May 21, 2018
14) Racioppi M, Di Gianfrancesco L, Ragonese M et al. Electromotive Drug administration ( EMDA) of mitomicyn C as first line salvage therapy in high risk “ BCG-failure “ non muscle invasive bladder cancer: 3 years follow-up outcomes”- BMC Cancer December 6, 2018 –
15) Di Modugno F, Pagliarulo V, Procacci A et al.Intravesical sequential BCG/Electromotive drug administration Mitomycin C ( EMDA-MMC ) in high risk non muscle invasive bladder cancer- results from a retrospective analysis,2018
16) Di Stasi SM, Riedl C, Updates in intravescical electromotive drug administration of mitomycin-C non-muscle invasive bladder cancer – World Journal of Urology, February 21st, 2009