Hyperthermia

PRINCIPLES OF HYPERTHERMIA& CLINICAL APPLICATION

MODERATOR : PROF. S.C.SHARMA

Definition Hyperthermia means elevation of temperature to a supraphysiological

level, between 40° to 45° C

Effects of Hyperthermia on Cell Survival :

- cause direct cytotoxicity

- kills cells in a log-linear fashion depending on

the time at a defined temperature

- initial shoulder region

- followed by exponential portion

- At lower temperatures,

resistant tail at end of heating period

The Arrhenius Relationship Defines temp dependence on rate of cell killing.

Temp vs log of slope (1/Do) of cell survival curve

biphasic curve

break point : For human cells : near 43.5 C

Significance :

above bk pt : temp Δ of 1 C , doubles rate of

cell killing

below bk pt : rate of cell killing drops by a factor of

4 to 8 for every drop in temp of 1 C

Basis for thermal dosimetry

Tumor temp varies during t/t Formula to convert all time temp data to equiv no. of minutes at a standard temp: CEM 43 C = tR (43-T)

where CEM 43°C = cumulative equivalent minutes at 43°C /thermal isoeffect dosedefined as time in minutes for which the tissue would have to be held at 43 C ,to suffer the same biologic damage as produced by actual temp, which may vary with time during a long exposure t = time of treatment T = avg temp during desired interval of heating R = 0.5 if temp >43 C & 0.25 if < 43 C

used to assess efficacy of heating

above 43 C : 1 C rise in temp: decreases time by a factor of 2:

so, t2/t1 = 2 (T1 – T2)

below 43 C : time decreases by factor of 4 -6 ,

so, t2/t1 = (4 to 6 ) T1 – T2

CEM at 43 C calculated by these expressions

Mechanisms of Hyperthermic Cytotoxicity

1. Cellular & tissue response

Primary target : protein (cell membrane, cytoskeleton, nucleolus)

cell killing by protein denaturation : heat of inactivation 130-170 kcal/mol

ultimate cell death : by apoptosis or necrosis

2. Physiological response

with temp increase

-Aerobic metabolism↑ (sensitive enzymes)

-Shift to anerobic metabolism (↓ATP &↑lactic acid)-Apoptosis ↑

Vascular: ↑ tissue perfusion ↑ microvessel pore size

ReoxygenationIncreased macromolecular & nanoparticle delivery.

↑ RT sensitivity & killing↑ antitumor effect of cct

Thermotolerance transient resistance to subsequent heating by initial heat treatment MECH:

Repair of protein damage via heat shock proteins (HSP) 70 -90 kd

2 ways of TT devlopment : At low temp 39 – 42 c --- during heating

Above 43 c ---- after heating stopped HOW TO AVOID TT?

minimum of 48 hours between hyperthermia fractions in order to decay TT LIMITATION:

- HT can’t be used every day with conventionally fractionated radiation

- many early trials utilized HT with RT #on schemes with large doses / fraction (e.g., 4 Gy per fraction, 2 to 3 times per week) -- higher n tissue complications & less total dose

FACTS:

- temp for radiosensitization : largely below that for cell killing

- heat radiosensitization : unaffected by thermotolerance,

- best way is take advantage of heat radiosensitization, rather than hyperthermic cytotoxicity,

and ignore the issue of TT

Modifiers of the Thermotolerance Response:

Thermal exposure above 43°C : TT during the heating prevented.

Step down heating:

- It is an initial short heat shock above 43 °C, followed by a drop in temperature

below this threshold, delays TT

- difficult to achieve clinically.

Acute reduction in pH, delays TT

Factors affecting response to hyperthermia Temperature

Duration of heating

Rate of heating

Temporal fluctuations in temperature

Environmental factors (pH & nutrient levels)

Combination with radiotherapy, chemotherapy, immunotherapy etc

Previous history

Intrinsic sensitivity

Effect of temperature:

NORMAL TISSUE (normal vasculature with rel. high ambient blood flow)

Vessels dilate Shunts open

Blood flow increases Heat carried away

INCRESED TEMP

TUMOR (rel. poor vasculature & unresponsive neovasculature)

Vessels incapable of shunting blood

Acts as heat ↓O2 ,

↓phresorvoir enhanced cell killing

Therefore, temp in tumor > than normal tissues with hyperthermia

Thermal sensitizers

1) acute acidification (decreasing ph)

a) induction of hyperglycemia

b) glucose combined with resp inhibitor MIBG (meta iodo benzyl guanidine),

c) pharmacologic agents that block the extrusion of hydrogen ions from cells,

2) decreasing tumor blood flow

a) hydralazine

b) nitroprusside

c) angiotensin II

d) nitric oxide synthase inhibitors (L-NAME)

risk of hypotension

Clinical hyperthermia achieved by exposing tissues to –

- Conductive heat sources

- Non – ionizing radiation – Electromagnetic(EM) -----RF, MW

Ultrasonic(US)

TECHNIQUES

SHORT WAVE DIATHERMY:

Therapeutic elevation of temperature in tissue by means of an oscillations of EM

energy of high frequency

Effect – local(increased tissue parfusion & increased metabolism)

- distant (reflux vasodilatation)

Duration: 10 – 15 min

Contraindicated in malignant tumors :

- large area heated

- no preferential tumor heating

ELECTROMAGNETIC HEATING

• Mech : Electric field passes through material : resistant heating occurs

• focus of heating broad : with low frequency & high wavelength

• can be invasive or non invasive

FOR SUPERFICIAL HEATING FOR DEEP HEATING

1 Microwave waveguides 1 Magnetic induction

2 Microstrip/ patch antenna 2 Capacitative coupling

3 Magnetic induction & capacitative coupling

3 Phased RF / microwave arrays

Depth treated

Power directed to tumor site

frequency (RF)

Coupling medium

Disadvantge

Microwave wave guide

Superficial 2-5 cm

By placing waveguide over tumor

433915 MHz2450

Deionized water bolus

-Limited depth t/t-Heating pattern not controllable

Magnetic induction

Deep> 5 cm

No; Magnetic field used

air -Eddy currents follow least resistance path

Capacitative coupling

Deep > 5 cm

By placing applicators / electrodes

5 – 30 MHz Saline bolus -supf fat heats-use in thin pts only

Microwave wave guide

Capacitative coupling

Radiofrequency phased array

Depth treated


frequency

Coupling medium

Disadvantge

Radiofrequency phased array

Deep > 5 cm

By altering phase & amplitude of power from different antennas

100 – 200 MHz Water bolus - Technically challenging

Array of RF antennas arranged in geometric pattern around target region

ULTRASOUND HEATING• Mech : energy transfer associated with viscous friction

FOR SUPERFICIAL HEATING FOR DEEP HEATING

Planar US transducers Focussed transducer arrays

Depth treated


US frequency

Coupling medium

Disadvantge

Planar US transducers

Superficial 2 – 5 cm

By placing transducer over tumor

1- 3 MHz Degassed water

- good coupling to body reqd- Air & bone inhibit penetration

Focussed transducer arraysSONOTHERM 1000

Deep > 5 cm

yes 0.5 – 2 MHz Degassed water

- Limited size of acoustic window- air & bone reflect power

Interstitial Hyperthermia- has same characteristics as interstitial radiation:

- highly localized & invasive

- WAYS:

a) simultaneous delivery

b) sequential heat and radiation(most clinical experience)

INTERSTITIAL HEATING TECHNIQUES :

a) low frequency RF electrode system (0.2 to 30 MHz)

b) high frequency MW antennas (300 – 1000 MHz)

c) hot source techniques

PRINCIPLE:

Usually combined with brachytherapy : double use of the implant for

both HT & RT

Radiofrequency waves (low frequency) - depth : to treat tumors 1-1.5 cm deep

- frequency : (0.2 to 30 MHz)

- technique : two or more implanted needle

electrode pairs(needle arrays)are

connected to a RF generator.

RF current (mobile ions) flows b/w oppositely polarized electrodes

- mech of heat transfer : Direct contact b/w metal electrodes & tissue required

(conductive current transfer)

- Limitation:

- requires close electrode spacing (1 to 1.5 cm) and regular geometry.

- Heating near electrodes causes treatment-limiting pain.

MicroWave interstitial heating (co axial antennas) depth : to treat tumors 1-1.5 cm deep

frequency : uses high frequency MW fields (300 – 1000 MHz)

technique : radioactive wires (Ir -192) & MW coaxial antennae introduced in same

catheter (nylon/ plastic catheter)

Antennas placed 1-1.5 cm from each other

mech of heat transfer :

current induction is predominantly capacitive (due to molecular

polarization) instead of conductive (due to free ion drift).

Hot Source Techniques-For tissues with low to moderate perfusion

TECHNIQUES:

1) electrical resistive heating elements

2) hydraulic systems that circulate heated water through tubes

3) ferromagnetic seeds that are heated externally via a time-varying magnetic

field (simplifies reheating of permanent implants)

THERMOMETRY Thermometry : procedure to measure intra-tumoral temperature

For supf tumors (< .5 cm) : probes attached on skin surface or mapped through catheters

lying on skin

For deep tumors: invasive thermometry is std.

Angiocath inserted in tumor at a point ,prependicular to the direction of electric flow

Temperature measured by putting a thermocouple probe in angiocath

Record: lowest thermal dose (lowest temp * time)

maximum thermal dose (highest temp * time)

Non invasive thermometry:

MRI is preferred technology- the MR parameters sensitive to temperature changes are:

relaxation times T1 & T2, bulk magnetization, resonance frequency of water atoms.

Hyperthermia and RadiationRationale for Combining the two:

1. Radioresistant cells in S-phase are most sensitive in hyperthermia

2. Hypoxic cells not resistant to hyperthermia.

3. lead to reoxygenation, further improve radiation response (RADIOSENSITIZER)

4. inhibits the repair of both sublethal and potentially lethal damage

Factors to Consider When Combining Hyperthermia with Radiotherapy

Effect of heat alone HT + RT

43-46 C – vascular destruction in highly perfused tissue

44 C - incresed thermal cytotoxicity (increased cell killing) X ray survival curve : steepening(↓ D0)

43 C – vascular destruction in poorly perfused tissue

40 – 43 C -No thermal cell killing -Thermal radiosensitization: -Improved nutrients & oxygen supply of radioresistant hypoxic cells -inhibited repair of XRT X ray survival curve : shoulder removed

41-42 C – cellular cytotoxicity enhanced at low ph & S phase

40 C – increased perfusion in all tissue types

36-38 C - normothermia Normothermia

1. Thermal Enhancement Ratio

- Interaction b/w radiation & hyperthermia can be quantified

- TER = ratio of doses RT / RT+HT to achieve isoeffect

- for therapeutic gain : TERtumor > TERnormal tissue

- TER ↑ with increasing heat dose

↓ with increasing time b/w RT & HT

- In most tumor types : TER is >1 for tumor control

- For normal tissues : TER is < than those for tumor

2. Excessively high temp (>45 C for 60 min) : normal tissue damage due to rapid tumor

regression -- chronic complications eg. Fibrosis, fistula

Evidence from randomized trials:

HT + RT ------ ↑ local control

No normal tissue late complications unless excessive intratumorall temp

Sequence of HT & RTSIMULTANEOUS HT + RT SEQUENTIAL HT + RT

(RT HT

Most evident: radiosensitizing effect

Hyperthermic cytotoxic mech predominates

Same effect on tumor & normal tissueUnless tumor temp> n tissue

Radioresistant hypoxic cells killed by HT t/t (but requires high temp)

When RT precedes HT – sensitization no longer detectable 2-3 hrs after RT

When HT precedes RT – cells can be sensitized for upto several hrs

No increase in TR Radiation dose decreasedTG achieved

Thermo tolerance develops HT t/t once/twice a week without altering radiation schedule

difficult More practical

Normal tissue response to :Heat Radiation

Cell death Apoptosis In attempting subsequent mitosis

Cells affected Differentiating + dividing

Only dividing cells

Repair mechanism Absent present

Hyperthermia and Chemotherapy

Rationale for combining the two:

Many chemotherapeutic agents demonstrate synergism with hyperthermia

Mechanisms:

(a) increased cellular uptake of drug

(b) increased oxygen radical production

(c) increased DNA damage and inhibition of repair

(d) reversal of drug resistant mechanisms

Factors to Consider When Combining Hyperthermia with Chemotherapy

MECHANISM DRUGSSYNERGISM WITH HT

cisplatin , melphalan, cyclophosphamide, anthracyclines, nitrogen mustards, hypoxic cell sensitizers, bleomycin, mitomycin C

COMMON MEMBRANE TARGET

Polyene antibiotics, local anesthetics, alcohol

TEMPERATURE DEPENDENCE

Topoisomerase inhibitors (temp up to 41.8°C increase activity of topoisomerase II)

REVERSAL OF DRUG RESISTANCE

cisplatin , melphalan , nitrosoureas , and doxorubicin

IMPROVE TUMOR OXYGN WITH RT

Tubulin binding agents, such as taxol

NO INTERACTION etoposide , vinca alkaloids, methotrexate

SEQUENCING For most drugs (excluding 5FU and other antimetabolites), esp platinum compounds optimal seq : administer them simultaneously or give drug imm. before heating.Continuous infusion of 5 FU & maintaining temp b/w 39 C & 41C – supraadditive effect

INCREASED DRUG DELIVERY:

- A liposome : small lipid vesicle (100 nm dia) ,contains water or saline in the center

- threshold for ↑ liposomal extravasation : 40°C,

- for 1 °rise upto 42 °C : rate of extravasation ↑ by factor of 2

>42 °C : vascular stasis and hge, reduces liposomal extravasation ↑ in liposomal extravasation at mod HT : exploited as a drug delivery vehicle

enhanced antitumor efficacy of a variety of drugs

In Doxorubicin-containing liposomes (very rapid 50% release of drug) at 40 °C) For drugs with mol wt <1000 : HT rel little effect

(diffusion : not temp dependent)

for molecules >1000 mol wt : HT augment extravasation of agents

monoclonal antibodies

polymeric peptides that can carry drugs

radioisotopes

Hyperthermia and Gene therapy

Under normothermic conditions: heat shock promoter : highly inducible & rel

quiescent

HT : by means of HSPromoters can control gene expression

eg: cells when transfected with adenovirus vectors containing HSP 70 promoter &

genes for green fluresence, IL 12, TNF alpha

heating to 42 °C for 30 minutes

several hundred-fold induction of above gene expression

Vernon multicentric trial (BREAST)- Included 5 phase III trials- Patients with chest wall recurrences

- Greatest benefit : Recurrent lesions in previously irradiated areas

RT n

HT +RT n

RT HYPERTHERMIANo. Thermal of # dose goal

End point

Breast n 306

135 171 29-50 Gy @ 1.8 - 4 Gy/# +- boost

1-8 Goal: T > 42.5 C every 30 min

CR: 59% vs 41% pActurial survival : 40% at 2 yrs in both

RTOG trial (1980) (SUPERFICIAL TUMORS)

- In superficial measurable tumors

- LIMITATION:

variable heating techniques

thermal dosimetry inadequacies

RT n

HT +RT n


End point

n = 307- H & N –50%-Breast cancers i.e chest wall recurrences – 33%- Others

117 119 32 gy/8# @ 4 gy/#

8 HT imm follows RT &Goal: 42.5 C for 45 - 60 min 2#/wk; “good” HT = 45 min at 42.5 C * 4#

Overall CRR: 32% vs 30% LCR for * lesions < 3 cm, * chest wall recurrenc 52% vs 25%

Datta single institute trial INDIA (HEAD & NECK)

RT n

HT +RT n


End point

Head & neck n 65

32 33 50 Gy / 25#@ 2 Gy/# + boost 10 -15 Gy to gross ds

twice a Goal: 20 min week at72 hr > 42.5 C interval

CR: 55 % vs 31% p at 8 wks with stage III & IVNo survival advantage seen

No benefit in Stage I / II patients: with > 90 % patients achieving CR with either t/t

Valdagni single institute trial ITALY (HEAD & NECK) Evaluated Locally advanced squamous cell carcinomas with metastatic cervical LN

RT n

HT +RT n


End point Effect of heating quality

Head & Neck(multiple nodes in some) n 44

23 21 64-70 gy @ 2 – 2.5 gy/#

2 vs 6 Goal: Tmin = 43 C every 30 min

CR: 82% vs 37% p at 3 mths

CR 86% vs 80% for 2 vs 6 HT doses;

No correlation b/w dose received & outcome

5 yr follow up on above patients

21/22 nodes

16/18 nodes

------------- 5 yr Acturial probability of LC in neck :69 % vs 24% p5 yr OS: 53 % vs 0 % p

Emami multicentre trial (RTOG STUDY) (INTERSTITIAL HYPERTHERMIA)- included 173 patients- With persistent/ recurrent tumors after prior RT / Surgery , amenable to IT HT

ITRT n

ITHT +ITRT n

INTERSTITIAL RT

HYPERTHERMIANo. Thermal of # dose goal


87 86 Prior dose + study dose < 100 Gy

1 or 2 Goal: Tmin 43 C for 60 min

CR: 57% vs 54% PR: 14% vs 24% (NOT SIGNIFICANT)

LIMITATION:Only 1 patient met criteria for adequate HT t/t

LED to RTOG guidelines for HTHead &

Neck45%

35 40 CR: 62 % vs 52 % PR: 10% vs 37 %LC: 43 % vs 37 %

Pelvis40%

37 38 CR: 60 % vs 57% PR: 10 % vs 8 %

Sugimachi single institute trial (ESOPHAGUS)

CRT n

HT +CCT + RT n


End point

Esophagus 66

34 32 30 gy/15#/@ 2gy/#

Bleomycin & HT given concurrently 1 hr prior to RT 3 weekly 6 Goal: 42.5 – 44 C every 30 min

Downstaging effect of Neoadjuvant therapyEffective in 69% vs 44% pPcr :26% VS 8% POS: 50 % vs 24% at 3 yrs

Esophagus 40

CCT alone

CCT + HT

6 Goal: 42.5 – 44 C every 30 min

Pcr :41 % VS 19 % P

Overgaard multicentric trial (MALIGNANT MELANOMA)

RT n

HT +RT n



Melanoma 128

65 63 24 – 27 Gy /3# @ 8 – 9 Gy/#

3 43 C for 60 min CR: 62% vs 35% p at 3 mths LC : 46% vs 28% p at 2 yrsRR : RT+HT vs RT alone CR = 4.01 2 yr LC = 1.73

LIMITATION:Only 14% patients achieved the goal of HT

BTboost n

ITHT +BT n

BT HYPERTHERMIANo. Thermal of # dose goal


GBMAfter RT 68

33 35 59.4 Gy /33# @ 1.8 Gy/#

2 median range CME 43C 14.1

TTP median:49 wk vs 33 wk p

8 patients received only 1 HT t/t

60 Gy @ 0.4-0.6 Gy/hrI -125 in 100 hrs

median range CME 43C T 50: 74.6

TTLTP :57 wk vs 35 wk p

2 yr OS:31% vs 15%

Median survival:85 wks vs 76 wks

Grade 3 Toxicity:7 patients vs 1

But no good thermal dose relationship found

Sneed single institute trial (GBM)Univ of California San Fransisco study

RT n

HT +RT n



361 176 182 1/wk ,upto 5 Target = 60 min after any point in tumor is 43 C

CR: 55% vs 39% at 3 mthsOS: 30% vs 24% at 3 yrs

41% patients received fewer than 5 HT t/ts due to refusal

Cervix 114

56 58 46-50 Gy @ 1.8-2 Gy/# + BT boost CR: 83% vs 57% pLC: 61 % vs 41 %P OS: 51 % vs 27%P

Max benefit seenamong pelvic tumors

Rectum 143

71 72 46-50 Gy @ 1.8-2.3 Gy/# + 10 -12 Gy boost

CR: 21% vs 15% LC: 38% vs 26% pOS: 13% vs 22%

Bladder 101

49 52 66-70 Gy @ 2 Gy/# CR: 73% vs 51% pLC: 42 % vs 33 % OS: 28 % vs 22%

Vander zee phase III trial DUTCH STUDY 1990 (PELVIS)

- Previously untreated LA pelvic tumors

Limitation: control arm RT alone received suboptimal therapy (no cct)

Sharma et al Randomized clinical studyPGI STUDY 1986 (CERVIX)

RT n

HT +RT n


End point

CA CERVIX(II & III)

25 25 45 Gy / 20#/4 wks@ 2.25 Gy/# + ICA with Cs 137 application (35 Gy to pt A)

thrice a Goal: temp week raised to 42-43 C over 15 min & maintained over next 30 min followed by RT after 30 min

LC: 70 % vs 50% p No survival advantage seen

Toxicity:Only minor , tolerable & manageable, not interrupting t/tNo late toxicity

Technique : endotract intravaginal applicator, active electrode, a larger extracorporeal indifferent electrode & a R.F generator operating at 27.12 MHzThermocouple fixed to inner surface of endotract applicator

Overgaard meta-analysis

22 trials

Compared risk of failure for pts treated with RT + HT vs RT

alone

Significantly ↓ed risk of failure in pts who received RT + HT

and p value of <0.00001

Clear evidence of benefit for melanomas, H& N, chest wall,

cervical, rectal & bladder cancers but no benefit for prostate

& intact breast cancers

HYPERTHERMIA TOXICITY

- HT toxicity (studies) with or without radiation is minor only

- Doesn’t result in treatment interruption

Thermal burns – generally grade I

Pain

Systemic stress

LIMITATIONS1. TECHNICAL CHALLENGES IN APPLICATION

- difficult for deep seated tumors

- invasive thermometry

- no recommended target temperature ranges to optimize HT t/t

- control of applied power

2. CONCURRENT CHEMORADIATION PROTOCOLS SUCCESS

- in increasing LCR of locally advanced cancers eg head & neck, cervix, colon

3. UPCOMING TARGETED THERAPIES

eg EGFR inhibitors in combination with RT

4. COMPETING TECHNIQUES

conformal techniques – selective dose delivery to desired target tissues

WHY HT STILL IN CONTINUED DEVELOPMENT PHASE?

1. Trimodality therapy (CCT + RT + HT) needed to achieve goal of 100% LC

2. Drug delivery to tumors remain a major challenge :

HT by increasing vascular permeability & volume fraction increase site specific

bioavailability

ex : Thermodox (temp sensitive liposome containing Doxorubicin) released rapidly

at temp of 40 C to 42 C

CONCLUSION

Hyperthermia is an useful adjuvant to radiotherapy & chemotherapy

Associated with increased local control rates with only minor/nil acute side effects

& no late toxicity

Major block : inability to heat designated TV of tissue & inadequate thermometry

Further advancement in HT technology needed to adequately utilize the gain

Thanks…

Hyperthermia and Metastases

Hyperthermia

- increased tumor perfusion

- changes in endothelial gap size

opportunity for enhanced tumor cell shedding. So local hyperthermia may enhance

the metastatic rate

exception of one study with the B16 melanoma, there is no evidence that local-

regional hyperthermia causes an increase in metastases

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Hyperthermia