6/19/2020

Combined Thermal and Radiotherapy for the Treatment of 45th Annual Meeting of the American Association of Medical Dosimetrists July 6, 2020

Dario Rodrigues, Ph.D. Assistant Professor of Thermal Oncology Physics University of Maryland School of Medicine Department of Radiation Oncology Division of Translational Radiation Sciences & Maryland Proton Treatment Center [email protected]

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Talk overview • Overview of cancer thermal

• Physics and biology of

• Superficial hyperthermia

• Deep hyperthermia

• Quality assurance

• Clinical evidence

• Future directions

“Those who cannot be cured by medicine can be cured by surgery. Those who cannot be cured by surgery can be cured by fire [hyperthermia]. Those who cannot be cured by fire, they are indeed incurable.”

—Hippocrates (460–370 B.C.) Until is cured 2

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Temperature goals for cancer thermal therapies Focus of today’s talk 150

100 Thermal Coagulation necrosis C)

° 50 44°C 39°C Hyperthermia 37°C Reversible Subtle Changes 0

-50 Temperature ( Temperature Cryotherapy Coagulation necrosis -100

-150

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Hyperthermia therapy (HT)

• HT refers to the treatment of malignant diseases by administering heat (39-44°C) via RF, MW, US, laser

Thermal • HT has been shown to enhance cell-killing effects of therapy radiation and/or cytotoxic drugs • HT is mostly a chemo- and radio-sensitizer Immuno- Surgery therapy Cancer • HT, by itself, is not enough to replace any of the Treatment conventional cancer therapies

• HT is applied 1-3 times/week 0-2 h before/after RT Chemo therapy • HT aims at improving the results of the conventional treatment strategies within the framework of multimodality treatments

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Adapted from Hyperthermia techniques Focus of today’s talk van der Zee et al. IJH 2008; 24(2):111-122 LOCOREGIONAL LOCAL INVASIVE Superficial Deep Radiative Intraluminal

Capacitive Interstitial Superficial Deep

REGIONAL WHOLE BODY Extracorporeal Circulation*

*Example: Hyperthermic Intraperitoneal

Until is cured Chemoperfusion (HIPEC) 6

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Biological rationale

• HT increases perfusion, permeability, pH, pO2

• HT is cytotoxic, including cells in the S-phase • HT suppresses DNA repair mechanisms • HT reduces tumor hypoxia

• HT increases drug uptake into tumor cells • HT overcomes various modes of drug resistance • HT increases delivery of macromolecules and drug carriers to tumors

• HT stimulates tumor-specific immune responses

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MW and RF hyperthermia

• Radiofrequencies (0.003-300 MHz) and Microwaves (300-300,000 MHz) are part of the electromagnetic spectrum with energies that are non-ionizing

Deep HT (70‐120 MHz) Superficial/Interstitial HT (915 MHz)

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EM wavelength and planewave penetration depth soft tissue

Tissue/Medium 100 MHz 915 MHz Air 300 33 Wavelength Fat 77 9 (cm) Bone cortical 84 10 Muscle/tumor 37 4

Deep Superficial HT (RF) HT (MW)

Note: USA uses 915 MHz and Europe uses 433 MHz due to allocated RF bands

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Heating mechanisms at RF

• Human tissue = lossy dielectric: a medium in which an EM wave loses power as it propagates due to poor conduction

• Heating mechanisms: • Dipolar polarization

• ∝ Relative permittivity (εr, no units)

100 MHz 915 MHz

• Ionic conduction • ∝ Electrical conductivity (σ, S/m)

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Hyperthermia – A multiphysics problem SAR = Specific Absorption Rate  • Maxwell Equations SAR || E 2 2 Units 3 ωb kg/s/m T SAR • HT in tissues ckTTcTTQTSAR  ()    W/kg tt t  b  b b met  3 t Qmet W/m

Index T  t tissue • HT in liquids ccTVkVSAR() ( )  wwt b blood met metabolism w water • Continuity equation Momentum equation

  V 2  V 0 VV p  Vf t Until is cured 12

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Blood perfusion in tumors

Song 1984 Cancer Res (mice data)

Rakedh 2001 Nat. Med.

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Thermal dose

Treatment time Temperature Thermal dose Effects (min) (°C) (CEM43) 60 39 0.2 Drug delivery 60 40 0.9 1 𝑡 , 𝑇43℃ 60 41 3.8 4 60 42 15 Chemo- 𝐶𝐸𝑀43℃ Radio- 𝑡 2 , 𝑇43℃ 60 43 60 Sensitization 60 44 120 60 45 240 Ablation 10 48 320 10 50 1280

HT goal: Thermal dose of ≥ 10 CEM43, for the HT course of txs • 40 min at 42°C • 10 min at 43°C • 5 min at 44°C Until is cured 14

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Deep Thermal Therapy Suite at Maryland Proton Treatment Center

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Sigma-Ellipse BSD-2000 equipment (51×38×48 cm3 ) • Applicator • Concentric ring RF phased array of 4 pairs dipole radiators • Forward power 0-2000 Watts (4 independent amplifiers) • Frequency 80-120 MHz • Phase & amplitude for 2D steering • Generates a fuzzy phase focus (hot spot) with Φ = 8-12 cm • Requires the use of a water bolus for cooling the surface and coupling energy from the antennas into the body Sigma-60 • Requires a RF shielded room (Ø=60 cm, L=48cm)

• Thermometry • 8 high-resistance carbon lead thermistors (RF-insensitive) • 2-3 internal (bladder, rectum and vagina) Tumor Surrogates • 5-6 external (spine, inner thigh, groin, abdomen, etc.) • Thermal mapping device with 8 channels • 0.5–1 cm increments along the tumor or at-risk tissue

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EM radiation hazards

• Exposure to high EM fields (>1 mW/cm2 for >6min) can lead to short-term immediate health effects Avoid permanence near • Stimulation of peripheral nerves and muscles the applicator (~60cm) • Electrical shocks and burns caused by touching conducting objects • Elevated tissue temperatures

• Even at very low exposure levels, chronic exposure can lead to • Production of stress proteins • Increased activity of free radicals • Calcium outflow • Increased permeability of blood-brain barrier • Platelet aggregation • Increased production of histamine • Etc.

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Effect of water loading on EM propagation

• The impedance of free space (air) is 377 Ω/sq and for water is 43 Ω/sq (9x lower) • The side of the dipoles with water represents a low impedance load that is considered to be in parallel with the loading of the high impedance air side. +V

Air Water The different impedance loading alone 377 Ω 43 Ω would direct about 9 times more power to the water side 1 Watt 9 Watts

-V • The BSD-2000 radiation field is selectively directed into the water bolus region and not into the outer air region because the dipole lengths (L) are too short for efficient radiation into air • L ≥ water = 28-42 cm (120-80 MHz) Dipole length of Sigma applicators (L) = 44 cm • L < air = 250-375 cm (120-80 MHz) Until is cured 19

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Deep hyperthermia treatments – Typical diagnosis and tx sites

Treatment Site

Diagnosis Relative # treatments # Relative

Rectum Pelvis Bladder Prostate Hip Vagina Relative # treatments # Relative

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SAR-based 2D treatment planning SAR = Specific Absorption rate (normalized)

80 MHz 120 MHz

(0,0) cm (0,0) cm

Patient Dimensions 110 MHz 110 MHz 19 cm × 33 cm

(0,3) cm (5,0) cm

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Deep HT - hyperthermia treatment planning (HTP) example 1

Position = (2,1) cm, frequency = 100 MHz %AMP = 100% Top, 100% Bottom, 100% Left, 100% Right

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Planning thermal mapping

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Planning thermal mapping – rectal and vaginal example

Rectum: Co=2cm, Ci=7cm

Vagina: Co=2cm, Ci=8cm

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Deep HT isocenter verification

4cm SUP of the pubic bone Until is cured 25

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Patient comfort strategies

Patient pillow armrest + External cooling (fan, wet cloths, ice packs) + Inner thigh water bolus cooling + Reading (distraction from 90min Tx) + Sedatives and analgesics if needed + Music per patient preference

↓

Maximize patient comfort

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Inner thigh water bolus

Circulating water bolus for inner thighs (15°C)

Reduce superficial hot spots ↓ Increase patient comfort

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Effect of inner thigh water bolus

Without thigh bolus With thigh bolus

Ta r g e t Ta r g e t

Inner thigh

Inner thigh

Target sensors • Bladder (Foley) Healthy tissue at high temperatures • Rectum (Mapping) limit higher target temperatures • Vagina (Mapping)

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Hyperthermia Equipment at UM-SOM

BSD 500 • Superficial/Interstitial targets • Applicator: 915 MHz rectangular waveguide • 8 temperature sensors • Water cooling/coupling system

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Deep hyperthermia treatments – Typical diagnosis and tx sites

Treatments by Primary Site

Treatments by Diagnosis txs of # Relative Relative # of txs of # Relative

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Superficial applicators and coupling water bolus • The only superficial heating system approved in the US is the BSD 500

MA 120 (18×24 cm2) MA 100 (10×13 cm2) Tx field 12.5×19.5×2.5 cm3 Tx field 8×10×2.5 cm3

MA 151 (4×5 cm2) Tx field 2.5×2.5×2 cm3

Conformal Bolus Rigid Frame Bolus Convex Surfaces Concave Surfaces

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Custom and conformal water bolus

68 yo male with recurrent 58 yo female with metastatic inflammatory breast Merkel cell carcinoma of forearm cancer. Bleeding lesions in breast, chest wall and across the back.

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Variables to Consider in Hyperthermia Tx Planning/Delivery

• Lateral extent and depth of disease/target • Temperature monitoring – probe positions

• Equipment/applicator • Input power • Applicator position

• Coupling bolus • Bolus shape • Bolus thickness • Bolus temperature

• Patient complaints (“outch factor”)

• Time for Hyperthermia Tx Planning!

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Arunachalam Effect of water bolus temperature in penetration depth PMB 2010

Treatment Depth > 40°C

38°C Bolus = 2.2 cm 42°C Bolus = 1.8 cm

Until is cured Perfusion = 2 kg/m3/s (moderate) 35 35

Validation of SAR simulations (%) in a muscle phantom Stauffer, Rodrigues, et al. Proc SPIE. 2017 100660:N1-15. 3 cm air coupling BSD frame bolus + 1.5 cm air

Measurements

MA 120 (18×24 cm2)

Simulations

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Rodrigues et al. 2015 IEEE Thermal modeling in biological tissues EuCAP; 7228886:1-5

• Simulations SAR + Temperature (Bioheat equation) • IT’IS Foundation tissue properties database v3.1

• Temperature dependent blood perfusion ωb 12 Skin 10 Muscle 8 ωb = ω0 ×F(T) F(T) Superficial 6 Tumors 4 basal blood perfusion Fat 2 (at normothermia)

0 37 38 39 40 41 42 43 44 45

Tissue temperature (°C) Until is cured 37

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Rodrigues et al. Effect of variable thickness bolus on heating profile STM 2017:115 Tissue Load • Skin: 1.5 mm • Fat: 15 mm • Muscle: 1 cm MA-120 Applicator 2 • Ribs: 7 × 25 mm 17 × 24 cm • Lung: 8 cm 3 • Tumor Target: Water bolus 21 × 28 × dbolus cm 14 × 20 × 1.65 cm3 Ta r g e t

Constraint:

• Tmax = 45C 41C Contour 40C Contour

Bolus cooling:

• Tbolus = 42C 2 • hbolus = 85 W/m /C

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Rodrigues et al. Effect of variable thickness bolus on heating profile STM 2017:115

°C Ta r g e t

Temperature-volume histogram in target

dbolus = 6 - 26 mm Pant = 125W

dbolus = 13 - 33 mm Pant = 175W

dbolus = 26 - 46 mm Pant = 150W Until is cured 39

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Routine QA - Equipment

• Power - BSD500 • Semi-Annual verification/recalibration output power x 8 channels • Power - BSD2000 • Semi-Annual verification/recalibration power and phase x 4 channels • Quarterly LED phantom SAR check for center & x,y +4 cm phase shift

• Temperature – BSD500 • Daily verification in calibration well (<0.2C) • Temperature – BSD2000 • Daily verification in water bath with transfer standard (<0.2C) • Semi-Annual recalibration in water bath with RTD standard • Daily thermal mapping visual inspection

• Additional QA on applicators and systems/bolus whenever operation in question

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QA - Lamp Phantom SAR Check Sigma Applicator

Central Focus Right Shifted Focus X, Y = 0, 0 X, Y = 0, +8 cm

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Reality check – quality assurance?

• Hyperthermia treatments are almost impossible to deliver as planned • Mainly because the coupling of energy sources to the tissue is often unpredictable • Last minute adjustments to the plan have to be made during tx delivery • Unpredictable blood flow changes cause distribution of heat which cannot be estimated in simulation treatment plans

• Treatment verification is a challenge • Sparse and fixed temperature locations • Sub-surface readings (interstitial) are not common

• Reproducibility and verification that the HT treatment met the intended goal are far more complex to document than radiation treatments.

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Jens Overgaard Effect of Increased TER on Clinical Response (Clinical Trials) Red J 1989; 16:535-549 Recurrent Breast Carcinoma of CW Malignant Melanoma

TER, Thermal Enhancement ratio

𝑅𝑒𝑠𝑝𝑜𝑛𝑠𝑒 𝑅𝑇 𝐻𝑇 Advanced H&N Nodes Advanced Breast Carcinoma 𝑇𝐸𝑅 𝑅𝑒𝑠𝑝𝑜𝑛𝑠𝑒 𝑅𝑇

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van Leeuwen et al. Timing of heat and radiation treatments (tRH) Rad Onc 2017 12(1):75 • Retrospective study on advanced cervical cancer patients (n=58) • Daily EBRT (23×2 Gy or 28×1.8 Gy) + 4-5 weekly locoregional HT at 70 MHz

53% 52% tRH > 79 min

t ≤ 79 min 18% 17% RH tRH ≤ 79 min

tRH > 79 min

• Findings • Minimize time between RT and HT • The majority of DNA damage was repaired within 2 h

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Randomized phase II/III superficial HT clinical trials: RT/CT vs RT/CT + HT

R/CT HT+R/CT 100 * previously irradiated 90 SUPERFICIAL HT 80 70 66 68 62 63 60 59 60 60 57 50 41 42 40 38 40 35 31 30 24

Complete Response (%) 19 20 10 0 Vagina Melanoma Breast Breast* Superficial Superficial* H & N Breast Kohno, Overgaard, Datta, IJH Datta, RedJ Vernon, RedJ 1996 Jones, JCO 2005 ICHO 1984 Lancet 1995 2016 2016

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Overgaard et al. Melanoma case study – 7 months follow-up IJH 1996; 12(1):3-20

A patient with a desmoplastic melanoma of the nose before (A), and seven months after (B) treatment with radiotherapy (5 6Gy) and hyperthermia (three treatments).

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Potencial side effects for superficial HT

• Pain at the site

• Infection Superficial

• Bleeding

• Blood clots

• Swelling

• Burns

• Blistering

• Damage to the skin, muscles, and nerves near the treated area

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Superficial HT risks - Hyperthermia toxicity

Insufficient temperature coverage  Dose Too High

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Randomized phase II/III deep HT clinical trials: RT/CT vs RT/CT + HT RT/CT HT+RT/CT 100 96 90 90 DEEP HT 80 76 70 68 60 62 60 53 54 50 50 50 40 31 29 30 24 20 Clinical Response (%) 20 15 13 15 10 8 0 Esophageal GBM Anal Anal Rectal Sarcoma Bladder Lung Cervical Kitamura, Sneed, Kouloulias, AJCO 2005 Haas-Kock, Issels, Colombo, Wang, Datta JSO 1995 RedJ 1998 (5y LRFS) Coch R 2009 Lancet 2010 BJUI 2011 MCO 2013 IJH 2016 (3y OS) (2y OS) (5y anorectal function) (CR) (CR+PR) (10y DFS) (CR+PR) (CR)

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Potencial side effects for deep HT

• Pain that is treatment limiting • Redness, tenderness, burns or blisters on the skin that is exposed to the device • Sub-dermal burn that can result in fat or muscle necrosis or induration • Infection/ulceration, usually caused by tumor necrosis • Infection/ulceration caused by catheter toxicity • Increased heart rate Deep • Increase or drop in blood pressure • Nausea/vomiting • • Osteonecrosis • Nerve impairment, including peripheral neuropathy, numbness, or cramping • Mucositis/edema/dermatitis • Diarrhea • Dysuria, spasms, hematuria • Heat stroke is a rare possibility

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New devices and treatment planning platforms SAR(%) Example: hyperthermia brain applicator

1) CT/MR scans

3) Patient-specific simulation and optimization of SAR and/or temperature for optimal T(°C) temperature coverage of the clinical target volume 2) Segmented CAD model

Until is cured Rodrigues 2019; STM Annual Meeting 54 54

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MR thermal image (MRTI) guidance during regional HT

MR thermometry map using the proton resonance frequency shift (PRFS) technique

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Future of hyperthermia

• Equipment • Equipment • Single applicators • Flexible and conformal arrays • Fixed geometry (hard shell) arrays • Increase number of radiators to improve focus

• Planning • Planning • Visual 2D applicator outline planning • Segmentation of individual patient anatomy • Pre-calculated generic patient 2&3D SAR • Patient-specific SAR and temperature simulations

• Monitoring • Monitoring • Sparse points or linear thermal maps • Realtime monitoring of 3D temperature maps

• Control • Control • Operator/patient pain manual feedback • 3D MRTI feedback for online SAR adjustment to produce uniform dose across tumor by end of treatment

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Parallels between hyperthermia and radiation therapies

Radiation therapy First treatment 1895 1981 Energy Ionizing radiation Non-ionizing MW/RF/US Primary effect DNA denaturation Radio/chemo-sensitization Tx planning Based on e.g. Monte Carlo (min) Based on FDTD and FEM (hours) Anatomy Anatomy & Physiology Tx simulation Yes No Tx frequency Daily 2x per week Tx time Few minutes >60 min Focus steering High precision (mm) Within cm Dose Gray = J/kg SAR = W/kg and CEM43 Dosimetry timing Before tx After tx Side effects Skin problems, fatigue, site-specific Blisters (sup.), discomfort (deep) Long-term side effects Acute side effects Physicist Certification Yes No

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Pathway to widespread of hyperthermia into Radiation and Medical Oncology clinics • Commercialize academic products that are decades ahead of available technology

• Formal practical training

• International consensus guidelines and standards for • Equipment QA • 3D treatment planning • Treatment delivery

• Certification of hyperthermia practitioners

Until is cured Thank you! Dario Rodrigues ([email protected]) 58 58

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