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

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

Jul 16, 2023 225 likes •624 views

RITE Thermo-chemotherapy for NON MUSCLE INVASIVE BLADDER CANCER (NMIBC) Ulrich K.Fr. Witzsch Klinik fr Urologie und Kinderurologie, Chefarzt Prof. Dr. med Dr. hc E. Becht Krankenhaus Nordwest, Stiftung Hospital zum Heiligen Geist 60488

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RITE FOIU, Tel Aviv, 05.07.2018 Witzsch

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

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RITE FOIU, Tel Aviv, 05.07.2018 Witzsch

Possible conflict of interest

  • Medical enterprise

– travel expense

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RITE FOIU, Tel Aviv, 05.07.2018 Witzsch

History

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RITE FOIU, Tel Aviv, 05.07.2018 Witzsch

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HIFU FU HYPER PERTHER ERMIA MIA  High gh Temp mperatur ture (>85 85 °C) C)  Shor

  • rt

t Time me (< 5 5 Sec.) .)  Low Temp mper eratur ture (< 45 45 °C) C)  Long ng Duratio tion (>1 1 Hr) Time me Temp mp.

Two differen ent t approa

  • ache

hes s to reach h the destruc uction tion thresho shold ld

Temp mp. Time me

Hyperthermia

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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
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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
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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

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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
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RITE FOIU, Tel Aviv, 05.07.2018 Witzsch

The aim

more MMC-Molecules permeate into the tumor cell and increase the effect

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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.

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RITE FOIU, Tel Aviv, 05.07.2018 Witzsch

Combat BRS HIVEC

COMBined Antineoplastic Thermotherapy Bladder Recirculation System Hyperthermic Intra-VEsical Chemotherapy (HIVEC™).

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Colombo et al. 2003/11 Kiss et al. 2015 Arends et al. 2016 Sousa et al. 2016 Tan et al. 2017 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 neoadjuvant 153 vs. 154 Risikoklassifikation

Intermediate- / high-risk, 1 CIS Intermediate -/ high-risk incl. CIS Intermediate - / high- risk incl. CIS Intermediate - / high-risk

  • incl. CIS

Intermediate – / high risk

Therapieschema

RITE: 2x20mg/50ml, 2x30 min, 8x wöchentl. + 4x monatl. MMC: 2x20 mg, 2x30 min, 8x wöchentl. + 4x monatl. 2x40mg/50ml, 2x 30min, 12x wöchentl. RITE: 2x20mg/50ml, 2x30 min, 6x wöchentl. + 6x alle 6 Wochen BCG: 6x wöchentl., 3x wöchentl. in Monaten 3, 6, 12 adjuvant: HIVEC/MMC 40mg/50ml, 60 min, 4x wöchentl. + 6x monatl. neoadjuvant: HIVEC/MMC 80mg/50ml, 60 min, 8x wöchentl. vor TUR HIVEC I: 40mg/50ml, 30 bzw. 60 min, 4x wöchentl. + 3x monatl. HIVEC II: 40mg/40ml, 60 min, 6x wöchentl.

Follow-up 24 Monate (2003) 50 Monate 26 Monate 24 / 37 Monate 24 Monate Überleben (RFS)

13

* Keine Langzeit-Nebenwirkungen festgestellt. ** Signifikanter Unterschied

Effectivity of chemo thermotherapy

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RITE FOIU, Tel Aviv, 05.07.2018 Witzsch

ASCO GU 2018

Vögeli et al

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Intravesikale Chemotherapie mit Hyperthermie SWDGU FFM, 23.06.2017 Witzsch

Synergo

Thermose nsoren Spülöffnung Antenne

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Synergo

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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.

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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

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Population

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high-risk patients(pTis, pT1 G3, NMIBC and BCG failures n=271)

Response rates

Induction phase Number Percent

  • No. Patients

271 Complete response 206 76.1 Partial response 21 7.6 No change 44 16.3

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Side effects

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Long term effect

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Maintanance optimises effect

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Comparison RITE vs BCG

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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%

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Synergo

EUROPEAN UROLOGY 69 (2016) 1046–1052 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 , *

(a) intention-to-treat and (B) per-protocol efficacy analysis sets

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Synergo

(a) intention-to-treat and (B) per-protocol efficacy analysis sets

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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

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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%).

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Synergo AUA2018

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Synergo AUA 2018

Progression 5% Progression 8%

Progression 8% Metastasis 5% Upper UT 6% Cystectomy 23% 10y OAS 54% 10y CSS 75%

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S3 Leitlinie

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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

  • ne 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

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NICE guideline

2015 not included 2018 will be included

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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

case

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RITE FOIU, Tel Aviv, 05.07.2018 Witzsch

45 y, male 2013 Instillationstherapie mit BCG (bis 12/13) 2014 BCGitis mit hepatischem und pulmonalem Befall, mehrmonatige tuberkulostatische Therapie 08/2015 TUR – B: multifokal pTa, low – grade 09/2015 TUR-B: keine Malignität Auswärtige Empfehlung zur Zystektomie mit Neoblase

case

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7x TUR-B in 3,5 y

  • 1. recurrance after Instillation with Mitomycin

severe BCGitis (hep pul) tuberculostatic therapy for several months 2.recurrance after. BCG

case

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RITE FOIU, Tel Aviv, 05.07.2018 Witzsch

11/2015 -01/2016 8 Induction Synergo (2x40 mg Mitomycin, weekly) 04 – 12/2016 6 Maintanance Synergo (2x20 mg Mitomycin 6-weekly). 3-monatliche Zystoskopien, since 03/17 Maintanance (2x20 mg Mitomycin, 3-monthly) 2,5 y recurrance free Side effects: urge 1x Botoxinjection 3 /18

case