14th Meeting of the EAU Section of Oncological Urology (ESOU)

Size: px

Start display at page:

Download "14th Meeting of the EAU Section of Oncological Urology (ESOU)"

Alison Barton
5 years ago
Views:

1 Is Bacillus Calmette-Guerin (BCG) still the best adjuvant treatment after Trans Urethral Resection (TUR) for Ta-T1 high grade (G3) bladder cancer M. Brausi, Modena (IT) Introduction Bacillus Calmette-Guerin (BCG) is considered the golden standard adjuvant therapy of Ta-T1 high grade (HGG3) transitional cell carcinoma (TCC) and for carcinoma in situ (CIS) of the bladder. However some recent reports show that alternative therapies can obtain better results in terms of recurrence and progression in this group of patients. Mitomycin C (MMC) is one of the most effective and utilized chemotherapeutic agents for prophylaxis in NMIBC. Due to its high molecular weight MMC rarely penetrates into the bloodstream and systemic side effects are rare. Enhancing the penetration of MMC into the bladder wall is certainly important for eradicating the tumor cells also in the tonaca propria and eventually in the muscularis mucosa. A technology that can obtain this is the electromotive administration of the drug (EMDA). The good results obtained with the administration of MMC with EMDA in low, intermediate and high risk patients after TUR have been reported extensively in literature. Also the efficacy of chemo- hyperthermia with MMC in intermediate, high risk and BCG resistant TCC of the bladder has been documented. The objective of this review is to demonstrate that the combination of immuno and chemotherapy administered with new technologies, Electromotive Drug Administration-EMDA and the use of Chemo-hyperthermia with MMC can obtain better results in terms of disease free interval and progression compared to BCG alone in patients at high risk. Material and Methods The use of sequential administration of immunotherapy and chemotherapy with EMDA has been reported and compared with BCG alone in high risk patients with TCC of the bladder. The median follow-up was 88 months. Patients treated with sequential BCG and electromotive MMC had higher DFI compared to patients who received BCG alone (69 mos vs 21 mos). The difference between the 2 groups was 48 months (log-rank p=0.0012). These patients had also a lower recurrence rate (41.9% vs 57.9%). The difference between groups was 16% (log-rank p=0.0012). Progression was 9.3% in the sequential group vs 21.9% in the BCG alone with a difference of 12.6% (log-rank p=0.004). Overall mortality was 21.5% vs 32.4% with 10.9% difference (log-rank p=0.045). Disease specific mortality: 5.6% vs 16.2%, difference between group was 10.6% (logrank p=0.01) (6). These important results were confirmed in a subsequent study by Gan et al. who treated 107 high risk patients with the same schedule and prospectively. The DFI after 2 year was 93%. Also the results of a randomised controlled trial comparing intravesical Chemohyperthermia with MMC versus BCG for adjuvant treatment of patients with intermediate and high risk TCC of the bladder showed a statistically significat better recurrence free survival (p = 0.08) in patients who received Chemohyperthermia. Conclusions BCG is still one of the most important and effective therapy in patients with high risk TCC of the bladder. However the sequential use of BCG and MMC with EMDA determined better results in terms of recurrence and progression compared to BCG alone. Also the use of Chemohyperthermia with MMC determines a higher RFS compared to BCG in this patients category. Future Guidelines should take into account these data and eventually modify their content. Eur Urol Suppl 2017; 16(2):94

2 Introduction Bacillus Calmette-Guerin (BCG) maintenance (3 years) is considered nowadays the golden standard adjuvant therapy for Ta-T1 High grade (G3) and carcinoma in situ of the bladder. (1). Is this still true? Do we have other possible alternative treatments showing better results in these high risk bladder cancer patients? The objective of this review is to demonstrate that the combination of immuno and chemotherapy administered with new technologies, Electromotive Drug Administration-EMDA and the use of Chemo-hyperthermia with MMC can obtain better response in terms of disease free interval and progression compared to BCG alone in patients at high risk. Background Mitomycin C (MMC) is one of the most effective and utilized chemotherapeutic agent for prophylaxis in NMIBC. Due to its high molecular weight MMC rarely penetrates into the blood stream and systemic side effects are rare. The local side effects consists in cystitis like symptoms and usually are mild. The mechanism of action of cytotoxic drugs in the bladder occurs mainly in the superficial layer, in the epithelial cells. Enhancing the penetration of MMC into the bladder wall is certainly important for eradicating the tumor cells also in the tonaca propria and eventually in the muscularis mucosa. A technology that can obtain this is the electromotive administration of the drug (EMDA). EMDA concept The epithelium of the urinary bladder is a major impediment to the passage of almost all solutes and drugs. Pharmacokinetics and pharmacodynamics of the chemotherapeutic drugs instilled into the bladder is very important to understand their mechanism of action. For most drugs, the diffusion coefficient across the urothelium approaches 0. Based on this, temporarily breaching the urothelial barrier and enhancing penetration of drugs in a controllable manner is an attractive concept. The technology for this approach is EMDA Lab studies, using freshly excised human bladder tissue, showed that EMDA accelerates the rate of transport of MMC across the urothelium by 6 to 9 times compared to passive diffusion (regularly adopted) (1). EMDA comprises 2 electrokinetic phenomena: Iontophoresis and electrophoresis. Iontophoresis is the active transport of ionized molecules into tissues by application of an electric current through a solution containing the ions to be administered at a rate defined by Faraday s Law: Ji = I(tr)/z F mol/s where I is the current (amperes), tr the proportion of applied current carried by I, and z the valency; F is Faraday s constant (2). Electrophoresis or electroosmosis is the transport of solutes in association with bulk movement of water. Drug transport rate (dd/dt) is the sum of that induced by passive diffusion (PD) and EMDA (dd/dt= PD +EMDA). However in presence of a membrane with at low permeability like the urothelium, EMDA is so dominant that it can be considered as the sole force manipulating drug transport. Therefore the administration rate of a drug is not only markedly increased but is controllable simply varying the current intensity (dd/dt = K. I). MMC carries virtually no charge and supplied with sodium chloride excipient. When current of positive polarity is applied to a solution containing Na+/C/MMC, sodium ions are intophoresed into underlying tissues, a process that includes transport of water in the form of hydration shells around Na+(2). Eur Urol Suppl 2017; 16(2):95

3 EMDA Apparatus The technology, produced by Physion (Mirandola, Italy) many years ago has been recently modified and up-dated. It is composed by: 1. A current source (Battery 12V, Physionizer 30) 2. An active electrode-receptacle containing the drug solution applied to the site of pathology (bladder) by a catheter 3. A dispersive (ground) electrode placed on the skin with patches (Fig 1). TreatmentModality The catheter with the electrode is inserted into the bladder which is drained and lavaged to remove residual urinary electrolytes. At this point MMC 40 mg in 100 ml of distilled water is administered. The electric current is ramped to ma and maintained at this level for minutes. Hyperthermia increases the anti-tumor drug uptake by neoplastic cells, increases the drug reaction rate and enhances the inhibition of DNA repair in damaged neoplastic cells. (Colombo R., Da Pozzo LF, Lev A et al.neoadjuvant combined microwave induced local hyperthermia and topical chemotherapy versus chemotherapy alone for superficial bladder cancer.. J Urol, 1996; 155: ). Hyperthermia in combination with instillation of the chemotherapeutic agent MMC has been proven to have greater complete response rates than intravesical chemotherapy alone, a reduced recurrence rate with acceptable rates of side effects.(colombo R. Da Pozzo LF, Salonia et al. Multicentric study comparing intravesical chemotherapy alone and with local microwave hyperthermia for prophylaxis of recurrence of superficial TCC: J Clin Onc. 2003; 21(23):4270-6) Clinical Experience In Table 1 are reported all the clinical studies with the use of EMDA with MMC available in literature. Intravesical MMC + EMDA has demonstrated an excellent safety profile and minimal toxicity at concentrations up to 40 mg/ml and for an instillation time up to 1-2 hours (3). The first clinical trial was a comparative phase II study on marker lesion. Twenty-eight patients with Tcc of the bladder at intermediate risk were recruited. MMC 40 mg + EMDA (15mA) for 20 once a week x 8 weeks vs MMC 40 mg for 2 hrs, same schedule was compared. The results showed a CR rate of 41% in both groups. However in responders a lower recurrence rate and a longer disease-free interval were observed in the EMDA/MMC group. Toxicity: 2/13 pts had chemical cystitis in EMDA Group (3). Di Stasi et al (4) randomized 3 groups of pts. with CIS to: MMC 40mg for 1 hour vs MMC+EMDA (20mA) for 30 vs BCG 81mg for 2hours. Schedule: the instillation were given once a week for 6 weeks and further 6 weekly treatments for non responders. Results MMC alone : CR = 31% MMC+EMDA: CR = 58% BCG: CR = 64% Eur Urol Suppl 2017; 16(2):96

4 In responders a lower recurrence rate and disease-free interval were observed in the EMDA group The peak plasma MMC was significantly higher following MMC+EMDA than after passive MMC (43ng/ml vs 8 ng/ml), supporting the hypothesis that EMDA of MMC increases tissue levels Toxicity: MMC+EMDA had less side effects than BCG. The combination of anticancer drugs given intravesically has not been applied extensively. The rationale behind it is a potential enhancement of the their activity. In 2006 the results of prospective randomized, controlled study with the sequential use of BCG and MMC with EMDA were reported by Di Stasi et al (5). Twohundred-twelve patients with multifocal T1G2 or T1G3 bladder cancer and Cis after TUR and re- TUR (73%) were randomly assigned to : BCG (81 mg) once a week for 6 weeks (105) or BCG (81 mg) once a week for 2 weeks followed by 40 mg MMC with EMDA (electric current 20 ma for 30 min) once a week as one cycle for 3 cycles. The total number of instillations was 9 with 6 BCG and 3 MMC with EMDA. Complete responders received a maintenance schedule: patients with BCG alone had 1 instillation a month for 10 months while those with sequential therapy had MMC 40mg +EMDA once a month for 2 months followed by BCG (81 mg) once a month as one cycle for 3 cycles. The total number of instillations in the BCG alone group was 16 vs 9 BCG and 9 electromotive MMC in the second group. The primary end point was disease-free interval (DFI). The secondary end point were time to progression, overall survival and cancer specific survival. An intention to treat analysis was performed. The median follow-up was 88 months. Patients treated with sequential BCG and electromotive MMC had higher DFI compared to patients who received BCG alone (69 mos vs 21 mos). The difference between the 2 groups was 48 months (log-rank p=0.0012). These patients had also a lower recurrence rate (41.9% vs 57.9%). The difference between groups was 16% (log-rank p=0.0012). Progression was 9.3% in the sequential group vs 21.9% in the BCG alone with a difference of 12.6% (log-rank p=0.004). Overall mortality was 21.5% vs 32.4% with 10.9% difference (log-rank p=0.045). Disease specific mortality: 5.6% vs 16.2%, difference between group was 10.6% (log-rank p=0.01). Toxicity: side effects were mainly local and there was no difference between the 2 groups. Three patients had to stop treatment for local and systemic side effects in both arms. A sub group analysis has been performed in patients with CIS that were evaluated separately. The results showed that the sequential therapy obtained higher response rate compared to BCG alone. The author s interpretation of the results was that BCG induced inflammation might increase the permeability of the bladder mucosa such that MMC can reach the target tissue more easily and exert its anticancer effect. The results of this study showing that the best possible treatment for high risk NMIBC is the sequential administration of BCG with electromotive MMC generated great discussions between urologists and a peculiar evaluation of the study has been performed. Different questions can be raised: 1. Would MMC alone (without electromotive administration) after BCG obtain the same results. The answer to this question can indirectly be found in the results of the phase I studies that clearly show a higher penetration of the drug into the bladder wall when an electric current is applied in contrast to the passive diffusion, 9 timed greater (1). 2. The better results obtained in the sequential group are due to the higher number of instillations administered (19 BCG + MMC/EMDA vs 16 BCG alone). The optimal maintenance schedule remain to be defined. Since the immune response to BCG fades away after about 6 months (6) a booster dose every 3 months seems reasonable. This could explain the results. Eur Urol Suppl 2017; 16(2):97

5 3. Re-TUR could had a positive impact on the results. Infact 29 patients were understaged and therefore the population treated was different from the ones reported in randomized prospective trials with BCG without Re-TUR (7). 4. Costs: sequential therapy is more expensive than BCG alone due to the added cost of MMC and the device (Physionizer and catheters). Gan et al (9) recently confirmed the Di Stasi results in the every-day practice reporting their experience with the use of sequential BCG/Emda/MMC, same schedule, which was adopted as the standard treatment for high risk NMIBC in their institution. They treated 107 patients with Ta-T1 high grade and Cis with a recurrence free rate at 2 years of 93%. There was no difference in recurrence between patients who received a full vs a reduced induction schedule. The rate of progression to MIBC in their unselected population was 3% at 2 years. The cost of EMDA/MMC and in particular the costs of sequential therapy has been debated and criticized. The administration of EMDA is more expensive than MMC or BCG alone due to the cost of the device (Physionizer) and catheters. Moreover the added costs of BCG and MMC/EMDA given sequentially is important. A contemporary costeffectiveness analysis comparing sequential BCG and electromotive MMC vs BCG alone for patients with high risk Ta-T1 and Cis has been done and reported recently (10). The final results showed that the reduction of recurrence and its delay determines a reduced number of TURs which are the mayor cost in the treatment of NMIBC. Therefore the authors concluded that the sequential therapy is a cost-effective treatment for patients with high risk Ta- T1 and Cis of the bladder In this moment different phase II/III randomized studies in Cis, Ta-T1 high grade have been designed and some are running world-while using electromotive MMC and BCG with the goal of confirming the data previously reported. Chemohyperthermia The Synergo system has been designed to deliver homogenous microwave hyperthermia in combination with instillation of MMC and was applied in both the adjuvant and ablative setting for the treatment of NMIBC. There is only one randomized study in literature comparing chemohyperthermia to BCG. Recently Arends et al reported the results of a randomized controlled trial comparing intravesical chemohyperthermia with MMC versus BCG for adjuvant treatment of patients with intermediate and high risk NMIBC. They treated 190 patients. Of them 29.2% were at high risk with 42 patients having primary or cuncurrent CIS. Treatment schedule: 1 year of chemotherapy-hyperthermia (1 a week for 6 weeks and 1 a month for 6 months) vs Y-year BCG (1 a week for 6 weeks and than 3 instillations at 3,6,12 months). Primary end point was : 24 months recurrence free survival (RFS) in the intention to treat (ITT) and per protocol (PP) analyses. Results: the 24-mo ITT RFS was 78.1% in the chemo group compared to 64.8% in the BCG group (p=0.08). The 24 mo RFS in the PP analysis was 81.8% in the chemo group vs 64.8% in the BCG group (p=0.02). Progression rates were < 2% in both groups. The study closed prematurely and thus is underpowered. The authors concluded saying that chemohyperthermia using Synergo System is an option for BCG therapy as adjuvant treatment for intermediate and high risk papillary NMIBC. Eur Urol Suppl 2017; 16(2):98

6 Conclusions The administration of MMC with EMDA is effective in CIS and when is administered in sequence after BCG is superior to BCG alone in high risk patients. ChemoHyperthermia with MMC determined better RFS than BCG in patients at intermediate and high risk. Further prospective randomized studies are needed to confirm these results. The guidelines committee should evaluate carefully these new data and eventually modify the previous statements. References 1. EAU Guidelines 2016 edition: 2. Di Stasi SM,Castagnola M, Vespasiani G et al: In vitro study of passive vs electromotive mitomycinc diffusion in human bladder wall. Preliminary results.j Urol 1994; 151:447A 3. Banga A and Chien YW. Iontophoretic delivery of drugs: fundamentals, developments and biomedical applications. J. Controlled Release 1988;7: Brausi M,Campo B, Pizzocaro G et al. Intravesical Electromotive Administration of Drugs for Treatment of Superficial Bladder Cancer: A Comparative Phase II Study. Urology 1998; 51 (3): Riedl CR, Knoll M, Plas E et al.intravesical electromotive drug administration technique:preliminary results and side effects. J Urol 1998; 159(6): Colombo R, Brausi M, Da Pozzo L 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; 391): Di Stasi SM, Giannantoni A, Stephen RL et al. Intravesical electromotive mitomycin C versus passive tran sport mitomycin C for high risk superficial bladder cancer: a prospective randomised study. J Urol 2003; 170: Di Stasi SM, Giannantoni A, Giurioli A et al. Sequential BCG and electromotive mitomyicin versus BCG alone for high risk superficial bladder cancer: a randomised controlled trial.lancet Oncol 2006 ;7: Kim JC and Steinberg GD: The limits of bacillus Calmette-Guerin for carcinoma in situ of the bladder. J Urol. 2001;165: Oddens J, Brausi M, Sylvester R. et al. Final results of an EORTC-GU cancer group randomized study of maintenance BCG in intermediate and high risk Ta-T1 papillary carcinoma of the urinary bladder:one-third dose vs full dose and 1 year vs 3 years of maintenance.eur Urol 2013; 63(3): Di Stasi SM, Valenti M, Verri C et al. Electromotive instillation of mitomycin immediately before transurethral resection for patients with primary urothelial non-muscle invasive bladder cancer: a randomized controlled trial. Lancet Oncol 2011; 12: Gan C, Amery S, Chatteron K et al: Sequential bacillus Calmette-Guèrin/Electromotive drug administration of Mitomycin C as the standard Intravesical regimen in high risk Nonmuscle Invasive Bladder Cancer: 2-year outcome. J.Urol 2016: 195: Eur Urol Suppl 2017; 16(2):99

7 13. Bachir BG, Dragomir A, Aprikian AG et al. Contemporary cost-effectiveness analysis comparing sequential bacillus Calmette-Guerin and electromotive mitomycin versus bacillus Calmette-Guèrin alone for patients with high-risk Non-Muscle-Invasive bladder cancer. Cancer 2014: 00 : 1-7 Fig.1 The new EMDA Apparatus (Physionizer, new designed catheter and electrodes with skin patches) Table 1. Update EMDA + MMC studies (Medline, April 2016) Pubblication Type of trial Treatment n Patients Tumor Brausi (3) RCT Therapeutic n = 28 Ta-T1 Phase II marker Riedl (4) Case series Prophilaxis n = 22 Ta-T1 and cis Colombo (5) non-rct Comparison n = 80 Ta-T1 Phase II marker Emda vs Synergo Di Stasi (6 ) RCT Prophylaxis n = 108 Cis Di Stasi (7) RCT Sequential bcg/emda n = 212 T1 and Cis HR Di Stasi (10) RCT Pre-op emda n = 374 Ta-T1 Gan (11) non-rct Sequential bcg/emda n = 108 Ta-T1 and Cis Bachir (12) retrospective Cost-effectiveness n = 212 Ta-T1 and Cis analysis Legend : RCT = Randomised Controlled Trial Eur Urol Suppl 2017; 16(2):100

NATIONAL INSTITUTE FOR HEALTH AND CLINICAL EXCELLENCE

NATIONAL INSTITUTE FOR HEALTH AND CLINICAL EXCELLENCE INTERVENTIONAL PROCEDURES PROGRAMME Interventional procedure overview of electrically-stimulated intravesical chemotherapy for superficial bladder