Hyperthermia

1. PRINCIPLES OF HYPERTHERMIA & CLINICAL APPLICATION MODERATOR : PROF. S.C.SHARMA

2. 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

3. 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

4. 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 dose defined 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

5. Mechanisms of Hyperthermic Cytotoxicity 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 Physiological response with temp increase - Aerobic metabolism↑ (sensitive enzymes) -Shift to anerobic metabolism ( ↓ATP & ↑lactic acid ) -Apoptosis ↑ Vascular: ↑ tissue perfusion ↑ microvessel pore size Reoxygenation Increased macromolecular & nanoparticle delivery. ↑ RT sensitivity & killing ↑ antitumor effect of cct

6. 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

7. 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

8. 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

9. 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 ↓O 2 , ↓ph resorvoir enhanced cell killing Therefore, temp in tumor > than normal tissues with hyperthermia

10. 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 

11. Clinical hyperthermia achieved by exposing tissues to – - Conductive heat sources - Non – ionizing radiation – Electromagnetic(EM) -----RF, MW Ultrasonic(US) TECHNIQUES

12. 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

13. ELECTROMAGNETI C 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

14. Depth treated Power directed to tumor site frequency (RF) Coupling medium Disadvantge Microwave wave guide Superficial 2-5 cm By placing waveguide over tumor 433 915 MHz 2450 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

15. Radiofrequency phased array Depth treated Power directed to tumor site 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

16. ULTRASOUND HEATING Mech : energy transfer associated with viscous friction FOR SUPERFICIAL HEATING FOR DEEP HEATING Planar US transducers Focussed transducer arrays Depth treated Power directed to tumor site 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 arrays SONOTHERM 1000 Deep > 5 cm yes 0.5 – 2 MHz Degassed water Limited size of acoustic window air & bone reflect power

17. 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

18. 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.

19. 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).

20. 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)

21. 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.

22. Hyperthermia and Radiation Rationale 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

23. 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

24. Thermal Enhancement Ratio - Interaction b/w radiation & hyperthermia can be quantified - TER = ratio of doses RT / RT+HT to achieve isoeffect - for therapeutic gain : TER tumor > TER normal 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

25. Sequence of HT & RT SIMULTANEOUS HT + RT SEQUENTIAL HT + RT (RT  HT Most evident: radiosensitizing effect Hyperthermic cytotoxic mech predominates Same effect on tumor & normal tissue Unless 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 decreased TG achieved Thermo tolerance develops HT t/t once/twice a week without altering radiation schedule difficult More practical

26. Normal tissue response to : Heat Radiation Cell death Apoptosis In attempting subsequent mitosis Cells affected Differentiating + dividing Only dividing cells Repair mechanism Absent present

27. 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

28. Factors to Consider When Combining Hyperthermia with Chemotherapy MECHANISM DRUGS SYNERGISM 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

29. 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

30. H yperthermia 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

31. 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 HYPERTHERMIA No. 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% p Acturial survival : 40% at 2 yrs in both

32. RTOG trial (1980) (SUPERFICIAL TUMORS) In superficial measurable tumors LIMITATION: variable heating techniques thermal dosimetry inadequacies RT n HT + RT n RT HYPERTHERMIA No. Thermal of # dose goal 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%

33. Datta single institute trial INDIA (HEAD & NECK) RT n HT + RT n RT HYPERTHERMIA No. Thermal of # dose goal 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 at 72 hr > 42.5 C interval CR: 55 % vs 31% p at 8 wks with stage III & IV No survival advantage seen No benefit in Stage I / II patients: with > 90 % patients achieving CR with either t/t

34. Valdagni single institute trial ITALY (HEAD & NECK) Evaluated Locally advanced squamous cell carcinomas with metastatic cervical LN RT n HT + RT n RT HYPERTHERMIA No. Thermal of # dose goal 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% p 5 yr OS: 53 % vs 0 % p

35. 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 HYPERTHERMIA No. Thermal of # dose goal End point Effect of heating quality 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 HT Head & Neck 45% 35 40 CR: 62 % vs 52 % PR: 10% vs 37 % LC: 43 % vs 37 % Pelvis 40% 37 38 CR: 60 % vs 57% PR: 10 % vs 8 %

36. Sugimachi single institute trial (ESOPHAGUS) CRT n HT + CCT + RT n RT HYPERTHERMIA No. Thermal of # dose goal 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 therapy Effective in 69% vs 44% p Pcr : 26% VS 8% P OS : 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

37. Overgaard multicentric trial (MALIGNANT MELANOMA) RT n HT + RT n RT HYPERTHERMIA No. Thermal of # dose goal End point Effect of heating quality 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 yrs RR : RT+HT vs RT alone CR = 4.01 2 yr LC = 1.73 LIMITATION: Only 14% patients achieved the goal of HT

38. BT boost n ITHT + BT n BT HYPERTHERMIA No. Thermal of # dose goal End point Effect of heating quality GBM After 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 /hr I -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

39. RT n HT + RT n RT HYPERTHERMIA No. Thermal of # dose goal End point Effect of heating quality 361 176 182 1/wk , upto 5 Target = 60 min after any point in tumor is 43 C CR: 55% vs 39% at 3 mths OS: 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% p LC: 61 % vs 41 %P OS: 51 % vs 27%P Max benefit seen among 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% p OS: 13% vs 22% Bladder 101 49 52 66-70 Gy @ 2 Gy /# CR: 73% vs 51% p LC: 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 )

40. Sharma et al Randomized clinical study PGI STUDY 1986 (CERVIX) RT n HT + RT n RT HYPERTHERMIA No. Thermal of # dose goal 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/t No late toxicity Technique : endotract intravaginal applicator, active electrode, a larger extracorporeal indifferent electrode & a R.F generator operating at 27.12 MHz Thermocouple fixed to inner surface of endotract applicator

41. 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

42. 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

43. LIMITATIONS 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 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 COMPETING TECHNIQUES conformal techniques – selective dose delivery to desired target tissues

44. WHY HT STILL IN CONTINUED DEVELOPMENT PHASE? Trimodality therapy (CCT + RT + HT) needed to achieve goal of 100% LC 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

45. 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

46. Thanks…

47. 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