T.J.H. Arends

Results of a Randomised Controlled Trial Comparing Intravesical Chemohyperthermia with Mitomycin C Versus Bacillus Calmette-Guérin for Adjuvant Treatment of Patients with Intermediate- and High-risk Non–Muscle-invasive Bladder Cancer

BACKGROUND Despite adjuvant intravesical therapy, recurrences in non-muscle-invasive bladder cancer (NMIBC) are still high; therefore, new treatment options are needed. The use of chemohyperthermia (CHT) as an alternative treatment is expanding in Europe. To date, however, there has been a lack of prospective randomised data. OBJECTIVE To compare CHT using mitomycin C (MMC) with bacillus Calmette-Guérin (BCG) as adjuvant treatment for intermediate- and high-risk NMIBC. DESIGN, SETTING, AND PARTICIPANTS Between 2002 and 2012, 190 NMIBC patients were randomised in this controlled, open-label, multicentre trial for 1-yr CHT (six weekly treatments and six maintenance treatments) and 1-yr BCG immunotherapy (six weekly treatments and three weekly maintenance treatments at months 3, 6, and 12). Patients and physicians giving the interventions were aware of assignment. This study is registered with ClinicalTrials.gov (NCT00384891). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS The primary end point was 24-mo recurrence-free survival (RFS) in the intention-to-treat (ITT) and per-protocol (PP) analyses in all papillary NMIBC patients (n=147). Analyses were done with the log-rank test and Fisher exact test. All tests were two-sided. RESULTS AND LIMITATIONS The 24-mo ITT RFS was 78.1% in the CHT group compared with 64.8% in the BCG group (p=0.08). The 24-mo RFS in the PP analysis was 81.8% in the CHT group compared with 64.8% in the BCG group (p=0.02). Progression rates were <2% in both groups. Regarding the side-effects, no new safety concerns were identified. A concern is that this study closed prematurely and thus is underpowered. Furthermore, blinding of treatment for patients and physicians was impossible; this may have resulted in unavoidable bias. CONCLUSIONS CHT is a safe and effective treatment option in patients with intermediate- and high-risk papillary NMIBC. A significantly higher 24-mo RFS in the CHT group was seen in the PP analysis. Based on the results above, CHT is an option for BCG therapy as adjuvant treatment for intermediate- and high-risk papillary NMIBC. PATIENT SUMMARY Recurrences in non-muscle-invasive bladder cancer are common, despite adjuvant therapies. We compared 24-mo recurrence-free survival (RFS) with chemohyperthermia (CHT) versus bacillus Calmette-Guérin (BCG) therapy. According to these data, CHT therapy appears to be safe and has higher 24-mo RFS than BCG therapy.

The effect of the time interval between diagnosis of muscle-invasive bladder cancer and radical cystectomy on staging and survival: A Netherlands Cancer Registry analysis

INTRODUCTION Data from single-center series suggest that a delay in time to radical cystectomy (RC) more than 3 months after diagnosis of muscle-invasive bladder cancer (MIBC) is associated with pathological upstaging and decreased survival. However, limited data is available from population-based studies. In this study, the effect of delayed RC was assessed in a nationwide cohort. MATERIALS AND METHODS Patients who underwent RC between 2006 and 2010 with primary clinical T2-T4N0M0 urothelial bladder cancer were selected using the Netherlands Cancer Registry database. Data from the Netherlands Cancer Registry was supplemented with data from the Nationwide Network and Registry of Histo- and Cytopathology database in case of incomplete information. The cohort was divided in patients who underwent RC ≤3 months (group I) vs. patients who underwent RC >3 months (group II). Median time from MIBC diagnosis to RC, variables associated with delayed RC >3 and the effect of delayed RC on staging and overall survival (OS) were evaluated in patients who underwent neoadjuvant therapy and patients who did not. RESULTS A total of 1,782 patients were included. Median follow-up time was 5.1 years for living patients and 1.3 years for deceased patients. Median time from MIBC diagnosis to RC was 50 days (interquartile range: 27 days) and 93% of patients underwent RC≤3 months. Patients older than 75 years (odds ratio [OR] = 0.50; 95% CI: 0.32-0.77), referred for RC (OR = 0.41; 95% CI: 0.26-0.69), and treated in a university hospital (OR = 0.34; 95% CI: 0.21-0.56) were less likely to undergo RC≤3 months. Pathologic upstaging rate (43.9% vs. 42.1%) and node-positive disease rate (20.2% vs. 21.7%) did not differ for group I and II. Delayed RC>3 months was not associated with decreased OS adjusting for confounding variables (hazard ratio = 1.16; 95% CI: 0.91-1.48; P = 0.25). Median time from MIBC diagnosis to RC in patients that received neoadjuvant therapy (n = 105) was 133 days (interquartile range: 62 days). Adjusting for confounding variables, delayed RC>3 months was not associated with OS (hazard ratio = 0.90; 95% CI: 0.45-1.82). CONCLUSIONS The vast majority of patient underwent RC within 3 months after diagnosis of MIBC, as recommended in the European Association of Urology MIBC guideline. Delayed RC for more than 3 months had no adverse effect on staging and survival.

Urinary cytokines in patients treated with intravesical mitomycin-C with and without hyperthermia.

ObjectivesTo explore whether urinary cytokine and chemokine (CK) levels differed between cold mitomycin-C (cold-MMC)-treated patients and chemohyperthermia (C-HT)-treated patients, to shed light on the possible molecular mechanisms that might explain the superior outcome of C-HT. Furthermore, CK-differences were explored between C-HT responders and C-HT non-responders.MethodsTwelve NMIBC patients were included. Nine received six-weekly C-HT, and three received four-weekly cold-MMC instillations. Urine was collected on 8–12 time points before and after every treatment. MDC, IL-2, IL-6, IL-8, IP-10, MCP-1 and RANTES were determined by Luminex®-analysis.ResultsElevated urinary CK levels were observed in both groups after treatment. In general, CK-peaks were lower in the cold-MMC group in comparison with levels in the C-HT group. Significant higher MCP-1 and IL-6 levels were observed in C-HT-treated patients. Additionally, significant cumulative effects were observed for IP-10 and IL-2. However, IP-10 and IL-2 levels did not significantly differ between treatments. MDC levels after the first week of treatment were significantly higher in the C-HT responders compared with the non-responders.ConclusionMMC treatment leads to elevated urinary CK levels with significantly higher MCP-1 and IL-6 levels in C-HT-treated patients. Increased MDC levels after the first C-HT instillation appear to be related to good clinical outcome and might be of additional value to personalize treatment. Studies involving more patients and longer follow-up are needed to substantiate this observation.

Intravesical radiofrequency induced hyperthermia enhances mitomycin C accumulation in tumour tissue

Abstract Introduction: Non-muscle invasive bladder cancer (NMIBC) is a highly recurrent disease with potential progression to muscle invasive disease despite the standard bladder instillations with mitomycin C (MMC) or Bacille Calmette–Guérin immunotherapy. Therefore, alternatives such as radiofrequency-induced chemohyperthermia (RF-CHT) with MMC are being investigated. The mechanism explaining the efficacy of RF-CHT is only partly understood. We examined whether RF-CHT results in higher MMC tissue concentrations as compared to cold MMC instillation. Patients and methods: Prior to a planned transurethral resection of bladder tumour (TURBT), patients with stage Ta NMIBC were allocated to either (1) cold MMC instillation or (2) RF-CHT. After MMC instillation, three biopsies were taken of both normal and tumour tissue. Biopsies were snap-frozen and MMC tissue concentrations were analysed using ultra-performance liquid chromatography. Results: Eleven patients were included of which six received RF-CHT. Ten patients had TaG2-LG/HG papillary tumours at pathology. One patient in the RF-CHT group appeared to be free of malignancy and was excluded from the analysis as no tumour biopsies were available. The median MMC concentration in tumour tissue was higher in the RF-CHT group (median 665.00 ng/g vs. 63.75 ng/g, U = 51.0, p = 0.018). Moreover, in both techniques the MMC concentration was lower in normal tissue compared to tumour tissue. Tissue MMC concentration measurements varied substantially within, and between, different patients from the same group. Conclusion: Intravesical RF-CHT results in higher tumour MMC concentrations vs. cold MMC instillation which contributes to its superior efficacy.

35 Intravesicale cytokines/chemokines na gecombineerde chemohyperthermie voor niet-spierinvasieve blaastumoren

SamenvattingIntravesicale chemotherapie gecombineerd met blaaswandhyperthermie (C-HT) is een veilige en effectieve behandeloptie voor patiënten met niet-spierinvasieve blaastumoren (NMIBC).

1 Recidiefvrije overleving van patiënten met intermediair- en hoogrisico nietspierinvasieve blaastumoren behandeld met chemohyperthermie of BCG. Een gerandomiseerde fase II-studie

SamenvattingHet recidiefpercentage bij niet-spierinvasieve blaastumoren (NMIBC) is, ondanks aanvullende behandelingen, hoog.

Radicale cystectomie voor blaascarcinoom: resultaten van een Nederlands hoogvolumecentrum

Resultaten In totaal werden 167 patiënten onderzocht. Cisplatinehoudende neoadjuvante chemotherapie werd gestart bij 126 patiënten. 41 patiënten voor wie cisplatine ongeschikt was, werden behandeld met een carboplatinehoudend schema. Complete klinische reponse (cCR) werd gezien bij 31,6% van de patiënten; partiële klinische response (cPR) bij 52,0% van de patiënten. Mediane overleving van de patiënten met een cCR was 49 maanden versus 17 maanden van de patiënten met een cPR. Bij 26,3% van de patiënten toonde histopathologie een complete pathologische response (pCR), met een mediane overleving van 74 maanden. Er was geen statistisch significant verschil in klinische en pathologische response tussen de cisplatineen de carboplatinegroep. Evenmin was er verschil in overleving.

Infectieuze complicaties na radicale cystectomie: een gedetailleerde analyse

Resultaten 96 patiënten werden geïncludeerd (gemiddelde leeftijd 65 jaar). De mediane tijd tussen de diagnostische CTen PET/CT-scan was 0 dagen (range 0-29 dagen). Bij 22% van de patiënten was het tumorstadium voor en na de PET/CT-scan verschillend. De PET/CT-scan leidde vaker tot upstaging dan downstaging (20% versus 2%, respectievelijk). Hierdoor veranderde de voorkeursbehandeling van 13 van de 96 patiënten (14%); 6 patiënten die gepland waren voor lokale behandeling werden geselecteerd voor neoadjuvante chemotherapie, en bij 7 patiënten werd van curatieve behandeling afgezien op basis van metastasen op de PET/CT-scan. De PET/ CT-scan detecteerde een tweede primaire maligniteit bij 8 patiënten. Hierdoor veranderde de behandeling van het blaascarcinoom bij nog eens 4 van de 96 (4,2%) patiënten. Alle laesies die leidden tot een beleidsverandering werden histopathologisch bevestigd.