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Abstract Background In case of high grade non-muscle invasive bladder cancer (HG-NMIBC), intravesical BCG represents the first-line treatment; despite the “gold” standard therapy, up to 50% of patients relapse, needing radical cystectomy. Hence, alternative therapeutic strategies have been developed. The aim of the study was to evaluate a first-lin...
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Context 1
... patients (15.4% of cases) underwent radical cystec- tomy for progression to muscle-invasive disease, in 3 cases (13%) for pT2 disease (1 patient had initial T1G3, 1 pa- tient had initial Cis, 1 patient had initial TaT1G3 + Cis) and in 1 case (3.8%) for pT4a (involvement of prostatic stroma at the level of prostatic urethra) (this patient had initial T1G3 + Cis) ( Table 2). ...
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Background:
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Citations
... There are currently no direct comparisons between EMDA ® -MMC and hyperthermic strategies such as RITE or HIVEC, either in terms of relative penetration into the bladder wall or in terms of oncological outcomes. Regarding the prognostic value of CIS, response rates to EMDA ® -MMC were significantly worse in the presence of CIS, with a disease-free survival rate of only 50% at 9 months in this subgroup of patients [30]. ...
CIS of the bladder is associated with a high risk of progression. In the case of BCG failure, radical cystectomy should be performed. For patients who refuse or are ineligible, bladder-sparing alternatives are evaluated. This study aims to investigate the efficacy of Hyperthermic IntraVesical Chemotherapy (HIVEC) depending on the presence or absence of CIS. This retrospective, multicenter study was conducted between 2016 and 2021. Patients with non-muscle-invasive bladder cancer (NMIBC) with BCG failure received 6–8 adjuvant instillations of HIVEC. The co-primary endpoints were recurrence-free survival (RFS) and progression-free survival (PFS). A total of 116 consecutive patients met our inclusion criteria of whom 36 had concomitant CIS. The 2-year RFS rate was 19.9% and 43.7% in patients with and without CIS, respectively (p = 0.52). Fifteen patients (12.9%) experienced progression to muscle-invasive bladder cancer with no significant difference between patients with and without CIS (2-year PFS rate = 71.8% vs. 88.8%, p = 0.32). In multivariate analysis, CIS was not a significant prognostic factor in terms of recurrence or progression. In conclusion, CIS may not be considered a contraindication to HIVEC, as there is no significant association between CIS and the risk of progression or recurrence after treatment.
... The authors report only three patients having experienced grade 3 adverse events, all for suspected bacteremia requiring hospitalization for intravenous antibiotic treatment. In a different study of EDMA in BCG-unresponsive disease, 60% of patients managed to retain their bladders avoiding cystectomy at year 3; however, three of 26 patients in that study had severe early allergic reactions to mitomycin C and underwent cystectomy [48]. Of note, EDMA is currently not available in the USA. ...
Purpose of Review
The treatment options for high-risk non-muscle invasive bladder cancer (NMIBC), particularly following BCG, remain limited. We highlight recent, promising therapies for high-risk NMIBC.
Recent Findings
Several therapies utilizing different mechanisms of action have demonstrated favorable results in the BCG-naïve and BCG-unresponsive settings. These treatments include intravenous and intravesical immunotherapy, viral- and bacterial-based intravesical therapies, combination intravesical chemotherapy regimens, and novel intravesical chemotherapy administration. Overall, the efficacy and tolerability of emerging treatments for NMIBC appear promising and provide potential alternatives to radical cystectomy.
Summary
As the landscape of managing BCG-unresponsive disease evolves, clinical trials will explore future options and determine effective alternatives.
... EMDA protocols adopted by the various centers show slight variations, with earlier studies using a lower current amplitude of 15 mA over shorter time periods of 20 min, while most subsequent studies utilize a maximum of 20 to 23 mA of pulsed DC applied over a duration of 30 min [47][48][49][50][51][52][53][54][55]. No differences in tolerability and adverse side effects were observed with the higher amplitude and longer durations. ...
... Amongst adjuvant studies, reported rates of complete response post-EMDA with MMC range from 40% to 82% while recurrence rates range from 14 to 52%. In addition, it was also found to have a potential role as salvage therapy in BCG refractory high grade NMIBC [55]. ...
Local-regional administration of cytotoxic drugs is an important adjunct to systemic chemotherapy amongst cancer patients. It allows for targeted delivery of agents at high concentration to target sites while minimizing systemic side effects. Despite the pharmacokinetic advantages of the local–regional approach, drug transport into tumor nodules remains limited due to the biophysical properties of these tissues. Electromotive enhanced drug administration (EMDA) represents a potential solution to overcome challenges in local drug transport by applying electric currents. Through electrokinetic phenomena of electromigration, electroosmosis and electroporation, electric currents have been shown to improve drug penetration and distribution in a wide variety of clinical applications. Amongst patients with non-muscular invasive bladder cancer (NMIBC) and basal and squamous cell skin cancers, EMDA has been successfully adopted and proven efficacious in several pre-clinical and clinical studies. Its application in ophthalmological and other conditions has also been explored. This review provides an overview of the underlying principles and factors that govern EMDA and discusses its application in cancer patients. We also discuss novel EMDA approaches in pre-clinical studies and explore future opportunities of developments in this field.
... We have established the parameters that permit to increase GNRs@Chit-Iso4 distribution on the top and lateral sides of the bladder, ensuring that targeted GNRs come into contact with any urothelial area in which the tumor might be located. Compared to other protocols such as the electromotive drug administration used to improve bladder wall penetration of Mytomycin C [49,50] or the use of a magnetic field to move silicon dioxide microparticles [48], US-assisted shaking from the abdomen is a safe, non-invasive protocol. ...
Detection and removal of bladder cancer lesions at an early stage is crucial for preventing tumor relapse and progression. This study aimed to develop a new technological platform for the visualization of small and flat urothelial lesions of high-grade bladder carcinoma in situ (CIS).
We found that the integrin α5β1, overexpressed in bladder cancer cell lines, murine orthotopic bladder cancer and human bladder CIS, can be exploited as a receptor for targeted delivery of GNRs functionalized with the cyclic CphgisoDGRG peptide (Iso4). The [email protected]Iso4 was stable in urine and selectively recognized α5β1 positive neoplastic urothelium, while low frequency ultrasound-assisted shaking of intravesically instilled [email protected]Iso4 allowed the distribution of nanoparticles across the entire volume of the bladder. Photoacoustic imaging of [email protected]Iso4 bound to tumor cells allowed for the detection of neoplastic lesions smaller than 0.5 mm that were undetectable by ultrasound imaging and bioluminescence.
... Another technique is the Electromotive Drug Administration (EMDA)-MMC, which exploits the phenomenon called "iontophoresis", created by intravesical electrodes, to improve the absorption of MMC. In a phase II trial enrolling patients with BCG-unresponsive NMIBC, EMDA-MMC demonstrated to have only a modest activity in CIS patients, while this system seemed to be effective in preventing the recurrence of papillary tumours (Ta or T1) [84]. ...
Non-muscle-invasive bladder cancer (NMIBC) is characterized by a high rate of cure, but also by a non-negligible probability of recurrence and risk progression to muscle-invasive disease. NMIBC management requires a proper local resection and staging, followed by a risk-based treatment with intravesical agents. For many years, the current gold standard treatment for patients with intermediate or high-risk disease is transurethral resection of the bladder (TURB) followed by intravesical bacillus Calmette–Guérin (BCG) instillations. Unfortunately, in about half of high-risk patients, intravesical BCG treatment fails and NMIBC persists or recurs early. While radical cystectomy remains the gold standard for these patients, new therapeutic targets are being individuated and studied. Radical cystectomy in fact can provide an excellent long-term disease control, but can deeply interfere with quality of life. In particular, the enhanced immune checkpoints expression shown in BCG-unresponsive patients and the activity of immune checkpoints inhibitors (ICIs) in advanced bladder cancer provided the rationale for testing ICIs in NMIBC. Recently, pembrolizumab has shown promising activity in BCG-unresponsive NMIBC patients, obtaining FDA approval. Meanwhile multiple novel drugs with alternative mechanisms of action have proven to be safe and effective in NMIBC treatment and others are under investigation. The aim of this review is to analyse and describe the clinical activity of new emerging drugs in BCG-unresponsive NMIBC focusing on immunotherapy results.
... 12 Historical data suggest that the risk of metastasis in patients with BCG failure reaches 50% after three additional cycles of BCG. 13 The need for novel bladder preserving therapies is therefore particularly acute for these patients. ...
... A small prospective study of 26 BCG-refractory patients reported a 12-month high-grade disease-free survival of 72% for patients with papillary tumors, and 38% for those with CIS. 13 Intravesical chemohyperthermia (CHT) can utilize external heating of the chemotherapeutic agent (combat bladder recirculation) or application of microwave energy to the bladder through a specialized catheter (Synergo) that heats the bladder wall to 41-44°C. 24 The latter device was used in a prospective study of patients with high and intermediate-risk NMIBC, 81% of whom had received prior BCG, to treat with MMC or epirubicin. ...
Non-muscle invasive bladder cancer (NMIBC) has traditionally been managed with transurethral resection followed by intravesical chemotherapy and/or bacillus Calmette–Guerin (BCG) in a risk-adapted manner. These tumors commonly recur and can progress potentially to lethal muscle invasive disease. A major unmet need in the field of NMIBC is bladder preserving therapy for recurrent high-grade NMIBC after adequate intravesical BCG therapy. The current gold standard treatment for these BCG-unresponsive patients is radical cystectomy, which is associated with considerable morbidity and mortality, particularly in older and frailer patients. It is therefore critical to provide alternative treatment options with acceptable oncological outcomes. In this review we explore novel bladder-sparing treatment options including combination intravesical therapy, enhanced instillation methods, immunotherapy, gene therapy, targeted therapy, photodynamic therapy and BCG variants across the spectrum of NMIBC disease states, ranging from low grade BCG-naïve patients through to high-grade BCG-unresponsive NMIBC.
... Three patients from each group withdrew from the study because of severe AEs [55]. To date, only one study has evaluated the efficacy of EMDA in BCG failure settings [56]. This prospective phase II trial enrolled 26 patients with recurrent high-grade NMIBC after BCG therapy. ...
... This prospective phase II trial enrolled 26 patients with recurrent high-grade NMIBC after BCG therapy. The high-grade recurrence-free survival was 61.5%, with a median follow-up duration of 36 months [56]. Of patients, 10 were finally treated with RC due to persistent high-grade disease (six patients, 23. ...
... Of patients, 10 were finally treated with RC due to persistent high-grade disease (six patients, 23. 1%) or progression to muscle-invasive stage (four patients, 15.4%) [56]. Three patients (11.5%) showed severe adverse systemic events of hypersensitivity to MMC with a hand-foot reaction, which caused treatment discontinuation. ...
Intravesical bacillus Calmette-Guérin (BCG) immunotherapy has been the gold standard adjuvant treatment for intermediate- and high-risk non-muscle-invasive bladder cancer (NMIBC) after transurethral resection of bladder tumor (TURBT). BCG immuno-therapy prevents disease recurrence and progression to muscle-invasive disease following TURBT. Although most patients initially respond well to intravesical BCG, considerable concern has been raised for patients with BCG failure who are refractory or recur in 6 months after their last BCG, which implies 'BCG-unresponsiveness'. Based on current clinical guidelines, early radical cystectomy (RC) is recommended to treat BCG-unresponsive NMIBC. However, due to the high risk of morbidity and mortality of RC and patients' desire to preserve their own bladder, there is a critical unmet need for alternative conservative treatments as bladder-sparing strategies in BCG-unresponsive patients. Trials for effective bladder-sparing treatments are ongoing, and several novel agents have been recently tested in the NMIBC setting. The goal of this review is to introduce and summarize recently reported novel and emerging drugs and ongoing clinical trials for BCG-unresponsive NMIBC.
... Racioppi et al recently published the results of a phase 2, single-arm study on 26 patients using EMDA-MMC (induction and maintenance) for highrisk NMIBC who failed BCG therapy. 311 Median followup was 36 months and HG disease-free rate was 61.5%. 311 In this study, a total of 10 patients underwent RC; of those, six (23.1%) had recurrent HG NMIBC and four (15.4%) had disease progression (three patients with pT2 and one with pT4a). ...
... 311 Median followup was 36 months and HG disease-free rate was 61.5%. 311 In this study, a total of 10 patients underwent RC; of those, six (23.1%) had recurrent HG NMIBC and four (15.4%) had disease progression (three patients with pT2 and one with pT4a). 311 Moreover, a retrospective study by Juvet et al evaluated 26 patients who failed BCG (all, except four were classified as BCG-unresponsive) and were treated with sequential BCG and EMDA-MMC. ...
... 311 In this study, a total of 10 patients underwent RC; of those, six (23.1%) had recurrent HG NMIBC and four (15.4%) had disease progression (three patients with pT2 and one with pT4a). 311 Moreover, a retrospective study by Juvet et al evaluated 26 patients who failed BCG (all, except four were classified as BCG-unresponsive) and were treated with sequential BCG and EMDA-MMC. 312 Complete response rates at six, 12, and 18 months were 62%, 44%, and 30%, respectively, while PFS at two years was of 48%. ...
Risk factors 1. Former or current tobacco smoking is the most common risk factor associated with bladder cancer and smoking cessation should be encouraged in all patients (Level of Evidence [LE] 3; strong recommendation). Symptoms and diagnosis 2. White-light cystoscopy (WLC) is recommended in the initial evaluation of patients suspected to have bladder cancer. Cystoscopy should be performed with a flexible cystoscope whenever available (LE 1; strong recommendation). 3. Urine cytology (voided or collected by bladder washing) is recommended as an adjunct to cystoscopy in patients suspected to have bladder cancer (LE 2; strong recommendation). 4. Upper urinary tract imaging is recommended in the initial workup of patients suspected to have bladder cancer (LE 3; strong recommendation). Prognostic factors for recurrence and progression 5. The most important prognostic factors for recurrence and progression of non-muscle-invasive bladder cancer (NMIBC) are stage and grade (LE 2). All patients with bladder cancer should be properly staged and, specifically for NMIBC, reporting grade is paramount for further management decisions (LE 2; strong recommendation). 6. Other prognostic factors are age >70yr, large tumour size (≥3cm), multiple tumours, the presence of concomitant carcinoma in situ (CIS), extensive invasion of the lamina propria, prior recurrence rates > 1 per year and status at first assessment after transurethral resection of the bladder tumour (TURBT) (LE 2), as well as lymphovascular invasion (LVI) (LE 3). 7. Aggressive histological variants such as micropapillary, plasmacytoid and sarcomatoid are associated with increased risk of under-staging and progression (LE 3). Pathological review, preferably by a dedicated uro-pathologist, should be considered in settings where variant histology is suspected or atypical tumours are seen during TURBT (e.g., sessile mass) (LE 3; weak recommendation). Risk stratification 8. All patients with NMIBC should be stratified according to the risk of both recurrence and progression for adequate patient counselling and treatment planning (LE 2; strong recommendation). The modified CUA risk stratification system is a suitable tool for this purpose. Transurethral resection 9. Patients presenting with a bladder tumour should undergo initial TURBT for diagnostic confirmation and pathological evaluation (LE 2; strong recommendation). 10. Initial TURBT aims for complete tumour resection with sampling of the underlying detrusor muscle as the first step of curative-intent treatment of NMIBC (LE 2; strong recommendation). Patients with presumed low grade (LG) Ta or CIS might be spared from muscle sampling at initial TURBT (LE 3; weak recommendation). 11. When available, blue light cystoscopy (BLC) (LE 1; weak recommendation) or narrow band imaging (LE 2; weak recommendation) can increase tumour detection at first TURBT and reduce recurrence risk. 12. A restaging TURBT should be performed in patients with T1 NMIBC, or when a complete resection was not achieved with the first TURBT (LE 2; strong recommendation). Restaging TURBT is not required in patients who will proceed to radical cystectomy (RC) based on the findings of the first TURBT. 13. In select cases of high grade (HG) Ta tumours (e.g., large and/or multiple tumours), a restaging TURBT can be considered (LE 3; weak recommendation). 14. The suggested window for a restaging TURBT is within 6 weeks of the first resection (LE 3; weak recommendation). 15. Patients presenting with a positive urine cytology, but normal appearing bladder at WLC and normal upper urinary tract imaging are at higher risk of harbouring occult CIS and should undergo random bladder biopsies (or use of BLC with directed biopsies) (LE 2; strong recommendation). 16. Biopsies or transurethral resection of the prostatic urethra should be included with random bladder biopsies in the presence of a positive bladder urine cytology, but normal appearing bladder at WLC and normal upper tract imaging (LE 3; strong recommendation). 17. Prostatic urethral biopsy (or transurethral resection) can also be considered in the presence of extensive bladder CIS or tumour at the bladder neck or trigone (LE 3; weak recommendation). 18. Patients with prostatic urethral involvement (PUI) with CIS restricted to the urethral mucosa can be managed conservatively with transurethral resection of the prostate (TURP) plus intravesical BCG (LE 3; weak recommendation). Repeat prostatic urethral biopsies after induction BCG should be considered (LE 3; weak recommendation). RC can be discussed as an alternative option (LE 4; weak recommendation). 19. In patients with HG T1 or CIS extending into the prostatic ducts, RC should be considered (LE 3; weak recommendation). TURP followed by intravesical BCG is an alternative option. In this instance, close followup with repeat prostatic urethral biopsies after induction BCG should be considered (LE 3; weak recommendation). 20. In patients with prostatic stromal invasion, neoadjuvant cisplatin-based chemotherapy followed by RC is recommended (LE 3; strong recommendation – refer to MIBC CUA guideline). Single instillation of chemotherapy (SIC) post-TURBT 21. SIC (with mitomycin-C, epirubicin, doxorubicin, pirarubicin or gemcitabine) should be offered to all patients with presumed low-risk NMIBC at TURBT and should be administered within 24 hours after endoscopic resection (LE 1; strong recommendation). 22. SIC is recommended for intermediate-risk NMIBC and for patients with ≤ 1 recurrence/year and EORTC recurrence score < 5 (LE 1; strong recommendation). SIC should be discussed even when further adjuvant intravesical chemotherapy is planned (LE 2; weak recommendation). 23. The benefit of SIC in patients with high-risk NMIBC is unclear when intravesical Bacillus Calmette-Guérin (BCG) is planned as adjuvant treatment (LE 3). 24. SIC should not be administered after extensive resection or when bladder perforation is suspected (LE 3; strong recommendation). Adjuvant intravesical chemotherapy 25. Patients with intermediate-risk NMIBC should be considered for adjuvant induction intravesical chemotherapy (LE 1; strong recommendation) with subsequent maintenance for up to 1 year (LE 3; weak recommendation), or induction BCG with maintenance therapy (refer to statement #30). 26. Substratification of intermediate-risk patients with recurrent LG Ta NMIBC can be used to guide adjuvant treatment decisions (LE 3; weak recommendation). For this purpose, 4 factors should be considered: number of tumours, size (≥ 3cm), time to recurrence (< 1 year) and frequency of recurrence (> 1/year). - Patients with low-intermediate-risk NMIBC (0 factors) may be treated similarly to low-risk patients, with SIC alone (LE 3; weak recommendation). - Patients with high-intermediate-risk NMIBC (≥3 factors) may be treated as high-risk patients with induction and maintenance BCG (LE 3; weak recommendation). 27. Patients who develop recurrence during intravesical chemotherapy may be offered induction followed by maintenance BCG (LE 3; weak recommendation). 28. Although intravesical chemotherapy through device-assisted therapy has shown promising results in small randomized controlled trials, further studies are needed to validate its routine clinical use. Adjuvant intravesical BCG 29. In patients with high-risk NMIBC, BCG therapy with induction (weekly instillations for 6 weeks) followed by 3-year maintenance (weekly instillations for 3 weeks at 3, 6, 12, 18, 24, 30 and 36 months) is the standard of care for reducing disease recurrence and progression rates (LE 1; strong recommendation). 30. When BCG is administered for intermediate-risk NMIBC, induction (weekly instillations for 6 weeks) followed by 1-year maintenance (weekly instillations for 3 weeks at 3, 6 and 12 months) is recommended (LE 1; strong recommendation). 31. RC with pelvic lymph node dissection is the standard of care for BCG-unresponsive bladder cancer in surgically fit patients (LE 3; strong recommendation). For patients with BCG-unresponsive CIS or HG Ta, a second-line bladder-preserving therapy can be considered before RC (LE 3; weak recommendation). 32. Promising efficacy has been reported with intravenous pembrolizumab, intravesical oportuzumab monatox, nadofaragene firadenovec, and BCG plus N-803. These should be considered as potential options in patients with BCG-unresponsive CIS who are unfit for or refuse to undergo RC (LE 2; weak recommendation). 33. Alternative options such as sequential intravesical gemcitabine/docetaxel (induction plus maintenance) may be considered for patients with BCG-unresponsive disease who are unfit for or refuse to undergo RC (LE 3; weak recommendation). Additional alternatives may also include other combination intravesical therapy (e.g., sequential gemcitabine/mitomycin-C, BCG + interferon if available) or single-agent intravesical therapy (mitomycin-C, epirubicin, docetaxel, gemcitabine) (LE 3; weak recommendation). 34. Clinical trials may be considered for BCG-unresponsive patients who are unfit for or refuse to undergo RC. Treatment adjustments only if BCG shortage 35. For patients with intermediate-risk NMIBC during BCG shortage, intravesical chemotherapy is recommended as the first-line option. If BCG is planned as a second-line therapy for this population, induction might be administered with reduced dosing (1/2 or 1/3 dose) and maintenance can be omitted (LE 3; weak recommendation). 36. For patients with high-risk NMIBC, full BCG schedule (induction followed by maintenance) is recommended (LE 1; strong recommendation). Only during BCG shortage, when full dose is not possible due to limited supply, dose reduction to 1/2 or 1/3 might be considered, while maintenance can be reduced to one year (LE 3; weak recommendation). 37. When BCG is unavailable, single agent chemotherapy (e.g., mitomycin-C, gemcitabine) or sequential combination of intravesical chemotherapy (e.g., gemcitabine/docetaxel) is recommended with induction followed by monthly maintenance for up to one year (LE 3; weak recommendation). Timely cystectomy 38. Upfront RC should be considered for patients with large volume, diffuse, endoscopically unresectable NMIBC (LE 3; strong recommendation) 39. Upfront RC should be offered to patients with HG T1 disease with additional adverse tumour pathological features including: variant histology (e.g., micropapillary, plasmacytoid, sarcomatoid), extensive invasion of the lamina propria or invasion into or beyond the muscularis mucosa (T1b/c), presence of LVI, concomitant CIS in the bladder or prostatic urethra, multiple and large (≥3cm) tumours, or persistent HG T1 upon restaging TURBT (LE 3; strong recommendation). Followup 40. The first surveillance cystoscopy is recommended for all patients at 3 months after TURBT (LE 2; strong recommendation). 41. A risk-based surveillance strategy should be used in patients with no evidence of recurrence at the 3-month cystoscopy: - Low-risk patients might be followed with cystoscopy at 1 year and then yearly for 5 years (LE 3; weak recommendation). Urine cytology is not necessary in the followup of low-risk patients (LE 4; weak recommendation). - Intermediate-risk patients should be followed with cystoscopies and urine cytology every 3-6 months in the first 2 years, every 6-12 months in the 3rd year, and annually thereafter (LE 3; weak recommendation). - High-risk patients should be followed with cystoscopies and urine cytology every 3-4 months during the first 2 years, every 6 months during years 3 and 4, and annually thereafter (LE 3; weak recommendation). 42. Upper tract imaging is recommended with random bladder/prostatic urethral biopsies (or use of BLC with directed biopsies) if positive urine cytology with normal WLC is found during surveillance (LE 3; weak recommendation). 43. Upper tract imaging is recommended in the first year and every 2 years thereafter for high-risk patients (LE 3; weak recommendation). 44. Fulguration under local anesthesia might be considered for small (<5mm) papillary tumours and negative cytology in patients with a prior history of papillary urothelial neoplasm of low malignant potential or LG Ta NMIBC (LE 3; weak recommendation).
... A posthoc analysis of a prospective trial with this platform showed 47% CR at 1 year in a BCG-unresponsive subset of 55 patients [36]. Further, a recent publication detailed proof-of-concept for electroMotive drug administration of Mitomycin C (EMDA-MMC) in 26 patients with NMIBC deemed BCG-refractory, although the number of patients with BCG-unresponsive NMIBC was not reported [37]. This technology utilizes a specialized catheter, which is connected to a generator to apply a directional current of drug towards the tissue. ...
Purpose of review:
Although radical cystectomy represents the gold standard treatment for patients with high-risk nonmuscle invasive bladder cancer (NMIBC) whose disease does not respond to bacillus Calmette-Guérin (BCG), many patients are unable or unwilling to undergo surgery. The need remains for effective bladder-preserving therapies. This review aims to describe existing treatments, contemporary research in this field and ongoing trials of salvage therapies for patients with BCG-unresponsive NMIBC.
Recent findings:
Intravesical chemotherapy has been utilized frequently in this setting. Emerging data on combination regimens such as intravesical gemcitabine and docetaxel and intravesical cabazitaxel, gemcitabine and cisplatin are promising; nevertheless, larger, prospective trials are needed. Meanwhile, the intravenous checkpoint inhibitor pembrolizumab was recently FDA-approved for patients BCG-unresponsive NMIBC. Encouraging clinical trial results for intravesical nadofaragene firadenovec, oportuzumab monatox and ALT-803 + BCG have been released, while data from trials of other treatment strategies, including novel chemotherapy and drug delivery, augmented BCG immunotherapy, adenoviral and gene therapy, targeted therapy, and combination systemic immunotherapy with intravesical agents, are eagerly awaited.
Summary:
Several novel salvage therapies offer promise for patients with BCG-unresponsive NMIBC. Patient selection, efficacy, safety, cost and ease of administration must be carefully considered to determine the optimal treatment approach.
... These treatments are deemed "electrically stimulated intravesical chemotherapy" or "electromotive drug administration (EDMA)." [23,24] Another well-known bioelectronic device is "Optune," which uses alternating electric fields (also known as tumor treating fields or TTFs) to halt the growth of cancer cells. This device is currently used as an adjuvant to standard-of-care chemotherapy in patients with newly diagnosed glioblastoma (grade IV astrocytic brain tumor) after treatment with surgery and radiation therapy. ...
Bioelectronic medicine is a treatment modality that uses electricity to treat disease by altering the body's electrical communication systems. All cells are electrically active, in that they possess bioelectric circuitry generating a resting membrane potential and endogenous electric fields that influence cell functions and communication. There is now an accepted paradigm that cancer is characterized by malfunctions in cells’ bioelectrical circuitry. This yields opportunities for bioelectronic medicine as novel treatments for cancer by manipulating its bioelectrical properties. To highlight the possibilities a bioelectrical approach can offer cancer therapy, the relevance of bioelectrical activity in cancer is reviewed and also how such activity can be hijacked in novel treatments. This includes sensing or measuring the electrical activity of cells for diagnostic and prognostic applications, controlling or altering bioelectricity including both ionic and faradaic current processes, and eliciting morphological changes using electric fields. Importantly, key links between cellular ionic and faradaic processes that contribute to cancer phenotypes are presented, which if considered and understood as a whole, can bring broad‐reaching improvements to cancer therapy.
