RITE Thermo-chemotherapy for NON MUSCLE INVASIVE BLADDER CANCER - PowerPoint PPT Presentation

RITE Thermo-chemotherapy for NON MUSCLE INVASIVE BLADDER CANCER (NMIBC) Ulrich K.Fr. Witzsch Klinik für Urologie und Kinderurologie, Chefarzt Prof. Dr. med Dr. hc E. Becht Krankenhaus Nordwest, Stiftung Hospital zum Heiligen Geist 60488 Frankfurt/Main Steinbacher Hohl 2- 26, Germany witzsch.ullrich@khnw.de RITE FOIU, Tel Aviv, 05.07.2018 Witzsch

Possible conflict of interest  Medical enterprise – travel expense RITE FOIU, Tel Aviv, 05.07.2018 Witzsch

History RITE FOIU, Tel Aviv, 05.07.2018 Witzsch

RITE FOIU, Tel Aviv, 05.07.2018 Witzsch

Hyperthermia Two differen ent t approa oache hes s to reach h the destruc uction tion thresho shold ld Temp mp. Temp mp. HIFU FU HYPER PERTHER ERMIA MIA Time me Time me 45 ° C) 85 ° C)  Low Temp mper eratur ture (< 45 C)  High gh Temp mperatur ture (>85 C)  Shor ort t Time me (< 5 5 Sec.) .)  Long ng Duratio tion (>1 1 Hr) RITE FOIU, Tel Aviv, 05.07.2018 Witzsch

Hypothesis of Hyperthermia  Acceleration of (bio)chemical processes  Hyperthermia  external  Warm liquid  internal  Direct cell damage  synergistic  stimulation of immunological response RITE FOIU, Tel Aviv, 05.07.2018 Witzsch

Hypothesis of Hyperthermia  Acceleration of (bio)chemical processes  Hyperthermia – external – Warm liquid – internal  Direct cell damage  synergistic  stimulation of immunological response RITE FOIU, Tel Aviv, 05.07.2018 Witzsch

Hypothesis of Hyperthermia  Selective death of cancer cells: – Cancer cells are more sensitive for heat  Vascular damage : – Neoangiogenesis is common in malignomas – New vessels are fragile – Heat leads to vasdilatation and vessel damage RITE FOIU, Tel Aviv, 05.07.2018 Witzsch

Hypothesis of Hyperthermia  Synergism of intravesical hyperthermia and chemotherapy • Increased binding of Mitomycin to DNA • More strandbreaks • Increased cell death of duplicating TCC cells • Increased permeability into the cell( spontaneous diffusion minimal MW – 332.4 kD) • Increased DNA sensitivity to heat RITE FOIU, Tel Aviv, 05.07.2018 Witzsch

The aim more MMC-Molecules permeate into the tumor cell and increase the effect RITE FOIU, Tel Aviv, 05.07.2018 Witzsch

Microwave www.nature.com/scientificreports Radiofrequency treatment alters cancer cell phenotype Matthew J. Ware Published: 13 July 2015 This suggested the malignant cells had undergone a form of radiofrequency shock. Non-malignant cells when subjected to a single RF treatment did not display any significant cytoplasmic retraction or detachment from the substrate surface. RITE FOIU, Tel Aviv, 05.07.2018 Witzsch

Combat BRS HIVEC COMBined Antineoplastic Thermotherapy Bladder Recirculation System Hyperthermic Intra-VEsical Chemotherapy (HIVEC™). RITE FOIU, Tel Aviv, 05.07.2018 Witzsch

Effectivity of chemo thermotherapy Colombo et al. Kiss et al. Arends et al. Sousa et al. 2016 Tan et al. 2017 2003/11 2015 2016 eau/AUA Poster Therapie RITE vs. MMC 40mg RITE RITE vs. BCG HIVEC HIVEC vs. MMC 40mg Patienten 41 vs. 42 21 72 vs. 60 14 adjuvant / 24 153 vs. 154 neoadjuvant Intermediate – / high Intermediate- / high-risk, 1 Intermediate -/ Intermediate - / high- Intermediate - / high-risk CIS high-risk incl. risk incl. CIS incl. CIS risk CIS Risikoklassifikation RITE: 2x20mg/50ml, 2x30 2x40mg/50ml, RITE: 2x20mg/50ml, adjuvant: HIVEC/MMC HIVEC I: 40mg/50ml, min, 8 x wöchentl. + 4x 2x 30min, 12x 2x30 min, 6x 40mg/50ml, 60 min, 4x 30 bzw. 60 min, 4x wöchentl. wöchentl. + 6x alle 6 wöchentl. + 6x monatl. wöchentl. + 3x monatl. Wochen monatl. MMC: 2x20 mg, 2x30 min, 8x neoadjuvant: HIVEC/MMC * Keine Langzeit-Nebenwirkungen festgestellt. wöchentl. + 4x monatl. BCG: 6 x wöchentl., Therapieschema HIVEC II: 40mg/40ml, 80mg/50ml, 60 min, 8x 3 x wöchentl. in 60 min, 6 x wöchentl. wöchentl. vor TUR Monaten 3, 6, 12 ** Signifikanter Unterschied 13 RITE FOIU, Tel Aviv, 05.07.2018 Witzsch Follow-up 24 Monate (2003) 50 Monate 26 Monate 24 / 37 Monate 24 Monate Überleben (RFS)

ASCO GU 2018 Vögeli et al RITE FOIU, Tel Aviv, 05.07.2018 Witzsch

Synergo Spülöffnung Thermose nsoren Antenne Intravesikale Chemotherapie mit Hyperthermie SWDGU FFM, 23.06.2017 Witzsch

Synergo RITE FOIU, Tel Aviv, 05.07.2018 Witzsch

Synergo Intravesical radiofrequency induced hyperthermia enhances mitomycin C accumulation in tumour tissue Conclusion: Intravesical RF-CHT results in higher tumour MMC concentrations vs. cold MMC instillation which contributes to its superior efficacy. RITE FOIU, Tel Aviv, 05.07.2018 Witzsch

Treatment  Induction phase – 2 x 40 mg Mitomycin per 30 Min with Hyperthermia 42 ° C 8 x weekly  Control – TUR- B 3 weeks after end of Induction phase  Maintanance – 2 x 20 mg Mitomycin per 30 Min with Hyperthermia 42 ° C 6 x every 6 Weeks  Control cystoscopy every 3 months RITE FOIU, Tel Aviv, 05.07.2018 Witzsch

Population RITE FOIU, Tel Aviv, 05.07.2018 Witzsch

high-risk patients(pTis, pT1 G3, NMIBC and BCG failures n=271) Response rates Induction phase Number Percent No. Patients 271 Complete 206 76.1 response Partial response 21 7.6 No change 44 16.3 RITE FOIU, Tel Aviv, 05.07.2018 Witzsch

Side effects RITE FOIU, Tel Aviv, 05.07.2018 Witzsch

Long term effect RITE FOIU, Tel Aviv, 05.07.2018 Witzsch

Maintanance optimises effect RITE FOIU, Tel Aviv, 05.07.2018 Witzsch

Comparison RITE vs BCG RITE FOIU, Tel Aviv, 05.07.2018 Witzsch

Synopsis  RIHTC has low side effects  CR after Induction 76,1% (206 of 271)  2y Progression free (CR) group 80,6% (160 of 206)  2y Progression free (all) 59% (160 von 271)  Calculated advantage vs BCG – 1y 241% – 5y 291% RITE FOIU, Tel Aviv, 05.07.2018 Witzsch

Synergo (a) intention-to-treat and (B) per-protocol efficacy analysis sets Results of a Randomised Controlled Trial Comparing Intravesical Chemohyperthermia with Mitomycin C Versus Bacillus Calmette-Guerin for Adjuvant Treatment of Patients with Intermediate- and High-risk Non – Muscle-invasive Bladder Cancer Tom J.H. Arends et al EUROPEAN UROLOGY 69 (2016) 1046 – 1052 , RITE FOIU, Tel Aviv, 05.07.2018 Witzsch *

Synergo (a) intention-to-treat and (B) per-protocol efficacy analysis sets RITE FOIU, Tel Aviv, 05.07.2018 Witzsch

ASCO GU 2018 Long-term results of organ preservation rate and progression risk in high-risk non-muscle-invasive bladder cancer (NMIBC) patients treated with radiofrequency-induced thermochemotherapy effect (RITE) with the Synergo system. Jill-Isabel Kilb, Arne Hauptmann, Florian Wagenlehner, Gerson Luedecke Induction 2x40, Maintanance 2x20 67 patients (4 female, 63 male), 65.7% Cis positive rate. 85% of the patients were treated alternatively to BCG with primary RITE 15% were BCG failure patients treated alternatively to indicated cystectomy RITE FOIU, Tel Aviv, 05.07.2018 Witzsch

ASCO GU 2018 Tumor persistence at week 11 after induction therapy proven by TURB was (10/67) 14.9% resulting in early cystectomy (4/10). Mean recurrence free time 3.5 years. In case of recurrence 10.4% progressed to MIBC incl- 6% metastatic tumors, high risk NMIBC was observed in 6% resulting in cystectomy low risk NMIBC recurrence was 1.5% with organ preservation. BC death rate was 1 out of 67. Incomplete treatments induced by SAE of RITE was 9% . Bladder preservation rate was 80.6% with a long-lasting effectiveness ( > 5 years) of 14/26 (53.8%). RITE FOIU, Tel Aviv, 05.07.2018 Witzsch

Synergo AUA2018 RITE FOIU, Tel Aviv, 05.07.2018 Witzsch

Synergo AUA 2018 Progression 8% Progression 5% Progression 8% Metastasis 5% Upper UT 6% Cystectomy 23% 10y OAS 54% 10y CSS 75% RITE FOIU, Tel Aviv, 05.07.2018 Witzsch

S3 Leitlinie RITE FOIU, Tel Aviv, 05.07.2018 Witzsch

EAU Guideline 2017 7.2.1.3.2.Device-assisted intravesical chemotherapy Hyperthermia Promising data have been presented on enhancing the efficacy of MMC using microwave-induced hyperthermia in patients with high-risk tumours [183]. In one RCT comparing one year of BCG with one year MMC and microwave- induced hyperthermia in patients with intermediate and high-risk bladder cancer, a reduced RFS at 24 months in the MMC group was demonstrated [184] (LE: 1b). Different technologies which increase the temperature of instilled MMC are available, however, data about their efficacy are still lacking. Recommendation: In patients with BCG-refractory tumours, who are not candidates for RC due to comorbidities, use preservation strategies (intravesical chemotherapy, chemotherapy and microwave-induced hyperthermia). Weak RITE FOIU, Tel Aviv, 05.07.2018 Witzsch

NICE guideline 2015 not included 2018 will be included RITE FOIU, Tel Aviv, 05.07.2018 Witzsch

case 45 y, male 01/2012 TUR – B: multifokal (4x) pTa, high - grade 03/2012 TUR – B: benigne 2012 Instillationstherapie mit Mitomycin (8x) 08/2012 TUR – B: benigne 02/2013 TUR – B: multifokal pTa, low - grade 04/2013 TUR – B: benigne RITE FOIU, Tel Aviv, 05.07.2018 Witzsch