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Safety and tolerability analysis of hyperthermic intravesical mitomycin to mitomycin alone in HIVEC I and HIVEC II: An interim analysis of 307 patients
... Adverse events. Similar to RITE, conductive hyperthermia therapy is well tolerated, and most adverse events are short-lived 80 (Table 4). Reliable adverse event data are available for the HIVEC system. ...
... Reliable adverse event data are available for the HIVEC system. An interim analysis of adverse events in 307 patients recruited into HIVEC-I and HIVEC-II reported that 89% of patients completed a minimum of induction therapy compared with 95% of patients treated with passive MMC 80 . In the patients treated with HIVEC, the most common adverse events were urinary frequency (15%), suprapubic pain (13.1%), haematuria (11.8%), and urinary urgency (11.8%) 80 . ...
... An interim analysis of adverse events in 307 patients recruited into HIVEC-I and HIVEC-II reported that 89% of patients completed a minimum of induction therapy compared with 95% of patients treated with passive MMC 80 . In the patients treated with HIVEC, the most common adverse events were urinary frequency (15%), suprapubic pain (13.1%), haematuria (11.8%), and urinary urgency (11.8%) 80 . HIVEC was associated with significantly increased incidence of urinary frequency (15.0% ...
Non-muscle-invasive bladder cancer (NMIBC), the most prevalent type of bladder cancer, accounts for ~75% of bladder cancer diagnoses. This disease has a 50% risk of recurrence and 20% risk of progression within 5 years, despite the use of intravesical adjuvant treatments (such as BCG or mitomycin C) that are recommended by clinical guidelines. Intravesical device-assisted therapies, such as radiofrequency-induced thermochemotherapeutic effect (RITE), conductive hyperthermic chemotherapy, and electromotive drug administration (EMDA), have shown promising efficacy. These device-assisted treatments are an attractive alternative to BCG, as issues with supply have been a problem in some countries. RITE might be an effective treatment option for some patients who have experienced BCG failure and are not candidates for radical cystectomy. Data from trials using EMDA suggest that it is effective in high-risk disease but requires further validation, and results of randomized trials are eagerly awaited for conductive hyperthermic chemotherapy. Considerable heterogeneity in patient cohorts, treatment sessions, use of maintenance regimens, and single-arm study design makes it difficult to draw solid conclusions, although randomized controlled trials have been reported for RITE and EMDA.
... Despite this, 7% of patients reported CTCAE Grade 1 bladder spams, 11% CTCAE Grade 1 urinary frequency/urgency, 24% CTCAE Grade 2 urinary frequency/urgency, 4% CTCAE Grade 1 urinary tract pain, 9% CTCAE Grade 2 urinary tract pain and 2% CTCAE Grade 3 urinary tract pain (3). Despite the low number of adverse events, the patients treated with HIVEC ® were significantly more likely to develop urinary frequency, haematuria and bladder spasm than passive mitomycin-C (4). The aim of this study was to analyse the role of two alkaloid, Protopine and Nuciferinein the prevention and the treatment of the low and mild grade adverse events related to the use of HIVEC ® instillations. ...
... This treatment might be a feasible option in BCG unresponsive NMIBC patients, potentially avoiding or postponing the need for radical surgery in a proportion of these patients (3,10,11). Nevertheless, this treatment can increase the rate of local adverse events than passive mitomycin-C like urinary frequency, haematuria and bladder spasm (4). Protopine has a demonstrated anti- cholinergic-antimuscarinic (11,12) and GABAergic (12)(13)(14)(15) action and it is able to influence some neurological systems responsible of bladder functions. ...
Objectives: The aim of this study was to analyse the role of two alkaloid, Protopine and Nuciferine, in the prevention and the treatment of the low and mild grade adverse events related to the use of HIVEC® (Hyperthermic IntraVEsical Chemotherapy) instillations.
Materials and methods: From September 2017 to September 2019, 100 patients were prospectively randomized into two groups: Group A = Protopine and Nuciferine syrup, 10 ml, once a day, for 8 weeks; Group B = placebo (flavoured coloured water), 10 ml, once a day, for 8 weeks. The primary endpoint was the evaluation of the efficacy of the therapy with Protopine and Nuciferine in controlling of the irritative symptoms. The secondary endpoint was the evaluation of the influences of the treatment on the uroflowmetric parameters.
Results: The patients of Group A showed a better International Prostatic Symptoms Score (IPSS) score, a better control of urgency symptoms (PPIUS) and tolerate well the pain (VAS score). The treatment doesn’t modify Uroflow-Qmax and seems to improve the Uroflow-Voided Volume (ml) without influencing the Uroflow-Post Void Residual volume (PVR). Moreover, the treatment with Protopine and Nuciferine has been proven to be effective in the treatment of overactive bladder (OAB) symptoms. Patients’ evaluation of the two different treatments assessed with Patient Global Impression of Improvement questionnaire (PGI-I), demonstrated improvements in the Group A, while the Group B showed a lower satisfaction.
Conclusions: Protopine and Nuciferine can be interesting nutraceutical compounds useful to control irritative and pain related symptoms of intravesical chemo/immunotherapy.
... The most common complications described were urinary frequency, haematuria and bladder spasms. Sometimes, allergic reactions were reported [5]. We aimed to assess the outcomes and complications of HIVEC treatment using two different drugs (Mitomycin-C [MMC] and Epirubicin [EPI]) that are commonly used for intravesical chemotherapy. ...
Introduction Chemohyperthermia is a feasible option in BCG (Bacillus Calmette-Guérin) failure patients
who desire bladder preservation. We aimed to assess outcomes and complications of chemohyperthermia using Mitomycin-C (MMC) or Epirubicin (EPI).
Material and methods From March 2017 to February 2020, 103 BCG failure or intolerance patients with
high-risk NMIBC (non-muscle invasive bladder cancer) underwent a Hyperthermic Intravesical Chemotherapy (HIVEC) regimen. Five patients did not complete at least 5 instillations and were excluded from analysis.
MMC was used in 72 out of 98 patients (Group A) while EPI was used in 26 patients (Group B). Response
to HIVEC, predictive factors for treatment outcome and the disease-free survival (DFS) were defined
as primary endpoints. The complications of chemohyperthermia were assessed as a secondary endpoint.
Results No significant differences were found in recurrence and progression after induction course between Groups A and B. Kaplan-Meier disease-free survival (DFS) was 22.61 months in Group A and 21.93
in Group B. The log-rank test showed no statistically significant difference between the two curves
(p = .627). In the multivariate analysis, patients with tumor size ≥3 cm (p = .029), recurrence rate >1/year
(p = .034), concomitant carcinoma in situ (CIS) during transurethral resection of bladder (TURB) (p = .039)
and BCG-unresponsive status (p = .048) were associated with a worse response to chemohyperthermia.
The use of MMC or EPI did not influence the response to treatment (p = .157). A slightly significant higher
rate of overall complications (p = .0488) was observed in Group B. A significantly higher rate of Grade 3
frequency/urgency (p = .0064) contributed to this difference. The use of EPI was the only independent
factor associated with severe urinary frequency/urgency (p = .017). No patients experienced Grade 4/5
adverse events.
Conclusions HIVEC can be considered a feasible option in BCG failure/intolerant NMIBC patients, avoiding
or postponing radical cystectomy in some particular subclasses of patients.
... Nos résultats méritent d'être confirmés de manière multicentrique. Si les résultats à venir des études prospectives randomisées de phase II HIVEC I (EudraCT 2013-002628-18) et HIVEC II (ISRCTN 23639415) devraient nous permettre de mieux apprécier l'efficacité de cette thermochimiothérapie par rapport à la Mitomycine passive dans les TVNIM à risque intermédiaire [13], d'autres essais sont actuellement en cours afin d'évaluer de façon rigoureuse son intérêt potentiel dans les TVNIM à risque élevé et/ou réfractaires au BCG. ...
Introduction:
There is increasing evidence that Hyperthermic Intravesical Chemotherapy is an effective treatment for non-muscle invasive bladder cancer (NMIBC). HIVEC (COMBAT BRS system) is an innovative hyperthermia delivering device. The aim of our study is to evaluate tolerance and safety of HIVEC in patients with BCG-refractory NMIBC.
Materials and methods:
In this study, we included 22 patients between January 2017 and April 2018. The treatment consisted in a weekly instillation of Hyperthermic Mitomycin for a total of 6 weeks, with a follow-up every 3 months. In order to evaluate the tolerance, patients filled a questionnaire before each instillation. We analyzed collected data to evaluate safety and efficiency of the treatment after one year.
Results:
Among 22 patients included, no patient suffered from severe side effects. The minor side effects reported were : urinary urgency (40,1 %), urinary pain (40,1%), macroscopic hematuria (4,5%). The IPSS score didn't significantly varied before and after instillations (mean IPSS: 10.8 versus 10.1, p=0.77). The mean follow-up was 11.2 months. The recurrence rate was 27,3% with an average time to recurrence of 7.36 months. Two patients (9.1%) presented a progression to muscle-invasive disease. Four patients (18,2%) had a radical cystectomy.
Conclusion:
Hyperthermic Mitomycin using the HIVEC® device is a rather safe and well tolerated treatment. Efficiency remains partial as 27.3% of patients experienced recurrence during the first year. These data should be confirmed by prospective multicentric studies.
... There is no difference in disease progression to MIBC [32,[36][37][38][39][40]. Regardless of RITE or conductive hyperthermic chemotherapy, most AEs are local and transient, and patients tolerate the treatment well [32,35,41]. Studies of conductive hyperthermic chemotherapy reported RFS rates of 65-87.5% at 24-month to 41-month follow-ups [36,[38][39][40], while in this study, the 24-month RFS was 82.9% (95% CI 74.4-91.4%) in the CTHC group, similar to or better than that reported previously. ...
Objective: To compare the efficacy and safety of a novel thermochemotherapy scheme and the instillation of pirarubicin (THP) without hyperthermia in patients with intermediate- and high-risk nonmuscle-invasive bladder cancer (NMIBC).
Materials and methods: Between June 2012 and December 2016, 300 patients with urothelial carcinoma of the bladder undergoing intravesical adjuvant therapy with THP after transurethral resection of bladder tumors (TURBT) were enrolled in the study. These patients were divided into the CTHC group (thermochemotherapy composed of three consecutive sessions in which only the second hyperthermia was combined with THP, followed by intravesical instillation with THP without using hyperthermia) and the THP group (instillation of THP without hyperthermia). Cystoscopy and urinary cytology were repeated every 3 months. The primary endpoint was 24-month recurrence-free survival (RFS). Secondary endpoints included 24-month progression-free survival (PFS) and adverse event (AE) rates.
Results: Baseline characteristics of the CTHC (n = 76) and THP (n = 85) groups were well-balanced. The 24-month RFS was 82.9% in the CTHC group and 63.5% in the THP group (log-rank p = .008). A significantly higher percentage of patients in the CTHC group achieved PFS than in the THP group (97.4% versus 87.1%; log-rank p = .011). There was no significant difference in AEs between the two groups (p > .05). Based on Cox proportional hazards models, CTHC was the only factor that contributed independently to improved RFS (hazard ratio, 0.422; 95% confidence interval, 0.214–0.835; p = .013).
Conclusion: The CTHC scheme is a safe and effective adjuvant treatment option after TURBT for patients with intermediate- and high-risk NMIBC.
... Thus, a specific catheter which is either well insulated or able to simultaneously cool the urethra is needed to be able to apply these temperatures in patients. A recent conference abstract on a clinically approved device for C-HT has evaluated these potential side-effects in intermediate risk NMIBC patients (n ¼ 307) and found no significant differences between C-HT and normothermic MMC on pain, dysuria, urgency, incontinence, nocturia, urinary tract infection, allergic reactions or urethral strictures [22]. Urinary frequency, hematuria, and bladder spasm were significantly more frequently observed after C-HT. ...
Introduction: Several techniques can be used to treat intravesical chemohyperthermia (ChHT). We compared radiofrequency-induced hyperthermia (RF-HT) with conductive hyperthermia (C-HT) for their ability to induce bladder wall temperatures of >40.5 °C, the target temperature for ChHT.
Materials and Methods: Fresh porcine bladders (n = 12) were placed in a temperature-controlled saline bath to simulate body temperature and circulation. HT was induced with RF-HT (43 °C) or C-HT (inflow temperature 44 and 46 °C) using a custom-made device. In two additional bladders, we varied intravesical solution and volume. Temperatures were recorded with a three-way catheter containing three mucosal and two urethral thermocouples (TCs) and a 915 MHz RF antenna, and with external TCs in the bladder wall at three different levels and three different locations.
Results: Target temperature (40.5 °C) was reached in the submucosa at all locations by both techniques. In the detrusor, target temperature was reached by RF-HT at the bladder neck and side wall. C-HT46 reached significantly higher submucosal temperatures at the side wall. The bladder dome seemed best heated by C-HT, although a high inflow temperature (46 vs. 44 °C) was required (ns). Intravesical saline resulted in higher temperatures than sterile water for RF-HT. A volume of 100 mL resulted in higher bladder dome temperatures for RF-HT, and higher bladder neck with lower dome temperatures for C-HT.
Conclusion: Our results indicate a slightly superior heating capacity for RF-HT compared to C-HT, whereas for the bladder dome, the reverse seems true. Comparative studies are warranted to evaluate whether HT efficacy differs between both techniques, with emphasis on tumor location.
Introduction:
Non-muscle-infiltrating cancers (NMIBC) represent 75% of bladder tumors. The objective of our study is to report a single-center experience of the efficacy and tolerability of HIVEC on intermediate- and high-risk NMIBC in adjuvant therapy.
Material and method:
Between December 2016 and October 2020, patients with intermediate-risk or high-risk NMIBC were included. They were all treated with HIVEC as an adjuvant therapy to bladder resection. Efficacy was assessed by endoscopic follow-up and tolerance by a standardized questionnaire.
Results:
A total of 50 patients were included. The median age was 70years (34-88). The median follow-up time was 31 months (4-48). Forty-nine patients had cystoscopy as part of the follow-up. Nine recurred. One patient progressed to Cis. The 24-month recurrence-free survival was 86.6%. There were no severe adverse events (grade 3 or 4). The ratio of delivered instillations to planned instillations was 93%.
Conclusion:
HIVEC with the COMBAT system is well tolerated in adjuvant treatment. However, it is not better than standard treatments, especially for intermediate-risk NMIBC. While waiting for recommendations, it cannot be proposed as an alternative to standard treatment.
Background: The efficacy of intravesical chemotherapy maintenance for patients with non-muscle invasive bladder cancer (NMIBC) is inferior compared to intravesical bacillus Calmette–Guerin (BCG). How intravesical chemohyperthermia (CHT) compares with BCG is under investigation.
Objective: To compare the oncological outcomes and safety profile between intravesical CHT and BCG treatment for intermediate- and high-risk NMIBC.
Methods: We performed a systematic review and meta-analysis of clinical studies comparing CHT with BCG for intermediate- and high-risk NMIBC patients. A comprehensive literature search on OVID MEDLINE, EMBASE, and Cochrane Library was conducted. Risk of bias was assessed by the Cochrane RoB tool and ROBINS-I. Certainty of evidence was rated using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology.
Results: A total of 2,375 articles were identified and five studies were finally included. Among them, four randomised trials comprising 327 patients (CHT group: 156 patients; BCG group: 171 patients) were included in the meta-analysis. There were no significant differences in the 24–36 months recurrence rates (CHT: 29.5%, BCG: 37.4%; RR: 0.83, 95% CI 0.61–1.13; moderate certainty of evidence) and the 24–36 months progression rates (CHT: 4.4%, BCG: 7.6%, RR = 0.62, 95% CI 0.26–1.49; low certainty of evidence). There were also no significant differences in grade 1–2 adverse events (CHT group: 59.9%, BCG group 54.5%; RR = 1.10, 95% CI 0.93–1.30; moderate certainty of evidence) and grade 3 or above adverse events (CHT group: 23.2%, BCG group 22.5%; RR = 0.99, 95% CI 0.69–1.43; low certainty of evidence).
Conclusions: Intravesical CHT had equivalent oncological outcomes and similar safety profile when compared to BCG maintenance therapy for patients with intermediate- and high-risk NMIBC. CHT is a possible alternative treatment in the times of BCG shortage.
Non-muscle-invasive bladder cancer (NMIBC) remains one of the most common malignancies and is associated with considerable treatment costs. Patients with intermediate-risk or high-risk disease can be treated with intravesical BCG, but many of these patients will experience tumour recurrence, despite adequate treatment. Standard of care in these patients is radical cystectomy with urinary diversion, but this approach is associated with considerable morbidity and lifestyle modification. As an alternative, perioperative intravesical chemotherapy is recommended for low-risk papillary NMIBC, and induction intravesical chemotherapy is an option for patients with intermediate-risk NMIBC and BCG-unresponsive NMIBC. However, poor pharmaceutical absorption and drug washout during normal voiding can limit sustained drug concentrations in the urothelium, which reduces efficacy, and small-molecule chemotherapeutic agents can be absorbed through the urothelium into the bloodstream, leading to systemic adverse effects. Several novel drug delivery methods - including hyperthermia, mechanical sustained released devices and nanoparticle drug conjugation - have been developed to overcome these limitations. These novel methods have the potential to be combined with established chemotherapeutic agents to change the paradigm of NMIBC treatment.
Adjuvant therapy with different bacillus Calmette-Guérin (BCG) preparations is a well-established guideline-endorsed treatment for nonmuscle invasive bladder cancer (NMIBC). Our observational study demonstrates equality between BCG and mitomycin C (MMC) treatment based on the oncological outcome. However, there were significant toxicity differences with higher rates in the BCG treatment group. The potential adverse effects of BCG in terms of a BCGitis are controversially discussed regarding their occurrence. As such, we sought to retrospectively evaluate the incidence in 106 consecutive patients. The BCG group demonstrated minor adverse effects in 78.4% and major adverse effects in 43.3%-partially coincident. Moreover, the parallel MMC group showed in 34.7% respectively 1.4% adverse events-as expected distinctly lower. In the context of this clinical discussion, we refer to alternative treatment concepts. Our data show a high clinical relevance of the patient's primary comorbidity.
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