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Hyperthermia
Hyperthermia, defined as elevating temperature above normal physiological levels, can be used to directly kill cancer cells or sensitize them to radiation and chemotherapy. Key points: - Temperatures of 40-45°C can directly kill cells in a time and temperature dependent manner. - Lower temperatures of 40-43°C do not directly kill cells but can sensitize them to radiation by improving oxygenation and inhibiting DNA damage repair. - Hyperthermia can also sensitize cells to chemotherapy by increasing drug uptake and oxygen radical production. - The combination of hyperthermia with radiation and chemotherapy has shown improved local tumor control compared to these treatments alone.
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 tempvaries 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 HyperthermicCytotoxicity 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 Vascular: -Aerobic metabolism↑ (sensitive enzymes) ↑ tissue perfusion -Shift to anerobic metabolism (↓ATP &↑lactic acid) ↑ microvessel pore size -Apoptosis ↑ Increased macromolecular Reoxygenation & nanoparticle delivery. ↑ RT sensitivity ↑ antitumor effect of cct & killing
- 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 theThermotolerance 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 responseto 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 TUMOR (normal vasculature with (rel. poor vasculature & rel. unresponsive neovasculature) high ambient blood flow) INCRESED TEMP Vessels incapable of shunting Vessels dilate blood Shunts open Acts as heat ↓O2 , ↓ph Blood flow increases resorvoir enhanced cell Heat carried away killing Therefore, temp in tumor > than normal tissues with hyperthermia
- 10. Thermal sensitizers 1) acuteacidification (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. TECHNIQUES Clinical hyperthermia achievedby exposing tissues to – - Conductive heat sources - Non – ionizing radiation – Electromagnetic(EM) -----RF, MW Ultrasonic(US)
- 12. SHORT WAVE DIATHERMY: Therapeuticelevation 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. 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 3 Phased RF / microwave arrays coupling
- 14. Microwave wave guide Capacitative coupling Depth Power directed frequency Coupling Disadvantge treated to tumor site (RF) medium Microwave Superficial By placing 433 Deionized -Limited depth t/t wave guide 2-5 cm waveguide over 915 MHz water bolus -Heating pattern not tumor 2450 controllable Magnetic Deep No; Magnetic field air -Eddy currents induction > 5 cm used follow least resistance path Capacitative Deep By placing 5 – 30 MHz Saline bolus -supf fat heats coupling > 5 cm applicators / -use in thin pts only electrodes
- 15. Radiofrequency phased array Array of RF antennas arranged in geometric pattern around target region Depth Power directed frequency Coupling Disadvantge treated to tumor site medium Radiofrequ Deep By altering phase & 100 – 200 MHz Water bolus - Technically ency > 5 cm amplitude of power challenging phased from different array antennas
- 16. ULTRASOUND HEATING • Mech : energy transfer associated with viscous friction FOR SUPERFICIAL HEATING FOR DEEP HEATING Planar US transducers Focussed transducer arrays Depth Power directed US Coupling Disadvantge treated to tumor site frequency medium Planar US Superficial By placing 1- 3 MHz Degassed - good coupling to transducers 2 – 5 cm transducer over water body reqd tumor - Air & bone inhibit penetration Focussed Deep yes 0.5 – 2 MHz Degassed - Limited size of transducer > 5 cm water acoustic window arrays - air & bone reflect SONOTHERM power 1000
- 17. Interstitial Hyperthermia - hassame 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 (lowfrequency) - 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 -Fortissues 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 Rationalefor 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 ConsiderWhen Combining Hyperthermia with Radiotherapy Effect of heat alone HT + RT 43-46 C – vascular destruction 44 C - incresed thermal cytotoxicity in highly perfused tissue (increased cell killing) X ray survival curve : steepening(↓ D0) 43 C – vascular destruction in 40 – 43 C -No thermal cell killing poorly perfused tissue -Thermal radiosensitization: -Improved nutrients & oxygen 41-42 C – cellular cytotoxicity supply of radioresistant hypoxic enhanced at low ph & S phase cells -inhibited repair of XRT 40 C – increased perfusion in X ray survival curve : shoulder removed all tissue types 36-38 C - normothermia Normothermia
- 24. 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
- 25. Sequence of HT& RT SIMULTANEOUS HT + RT SEQUENTIAL HT + RT (RT HT Most evident: radiosensitizing Hyperthermic cytotoxic mech effect predominates Same effect on tumor & normal Radioresistant hypoxic cells killed tissue by HT t/t (but requires high temp) Unless tumor temp> n tissue 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
- 26. Normal tissue responseto : Heat Radiation Cell death Apoptosis In attempting subsequent mitosis Cells affected Differentiating + dividing Only dividing cells Repair mechanism Absent present
- 27. Hyperthermia and Chemotherapy Rationalefor 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 ConsiderWhen Combining Hyperthermia with Chemotherapy MECHANISM DRUGS SYNERGISM WITH cisplatin , melphalan, cyclophosphamide, anthracyclines, nitrogen HT mustards, hypoxic cell sensitizers, bleomycin, mitomycin C COMMON Polyene antibiotics, local anesthetics, alcohol MEMBRANE TARGET TEMPERATURE Topoisomerase inhibitors (temp up to 41.8°C increase activity of DEPENDENCE topoisomerase II) REVERSAL OF cisplatin , melphalan , nitrosoureas , and doxorubicin DRUG RESISTANCE IMPROVE TUMOR Tubulin binding agents, such as taxol OXYGN WITH RT 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. Hyperthermia and Genetherapy 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 RT HT RT HYPERTHERMIA End point n + No. Thermal RT of # dose goal n Breast 135 171 29-50 Gy 1-8 Goal: T > 42.5 C CR: 59% vs 41% p n 306 @ 1.8 - 4 every 30 min Acturial survival : Gy/# +- 40% at 2 yrs in boost both - Greatest benefit : Recurrent lesions in previously irradiated areas
- 32. RTOG trial (1980) (SUPERFICIAL TUMORS) - In superficial measurable tumors RT HT RT HYPERTHERMIA End point n + No. Thermal RT of # dose goal n n = 307 117 119 32 gy/8# 8 HT imm follows Overall CRR: - H & N –50% @ 4 gy/# RT &Goal: 42.5 C 32% vs 30% -Breast cancers for 45 - 60 min LCR for i.e chest wall 2#/wk; “good” * lesions < 3 cm, recurrences – HT = 45 min at * chest wall recurrenc 33% 42.5 C * 4# 52% vs 25% - Others - LIMITATION: variable heating techniques thermal dosimetry inadequacies
- 33. Datta single institutetrial INDIA (HEAD & NECK) RT HT RT HYPERTHERMIA End point n + No. Thermal RT of # dose goal n Head & 32 33 50 Gy / twice a Goal: 20 min CR: 55 % vs 31% p neck 25# week at at 8 wks n 65 @ 2 Gy/# 72 hr > 42.5 C with stage III + boost 10 interval & IV -15 Gy to No survival gross ds advantage seen No benefit in Stage I / II patients: with > 90 % patients achieving CR with either t/t
- 34. Valdagni single institutetrial ITALY (HEAD & NECK) Evaluated Locally advanced squamous cell carcinomas with metastatic cervical LN RT HT RT HYPERTHERMIA End point Effect of heating n + No. Thermal quality RT of # dose goal n Head & 23 21 64-70 gy 2 vs 6 Goal: Tmin = 43 C CR: 82% vs 37% p CR 86% vs 80% for Neck @2– every 30 min at 3 mths 2 vs 6 HT doses; (multiple 2.5 gy/# nodes in No correlation some) b/w dose received n 44 & outcome 5 yr 21/ 16/18 ------------- 5 yr Acturial follow 22 nodes probability of LC up on no in neck : above des 69 % vs 24% p patients 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 ITHT INTERSTIT HYPERTHERMIA End point Effect of heating n + IAL RT No. Thermal quality ITRT of # dose goal n 87 86 Prior dose 1 or 2 Goal: Tmin 43 C CR: 57% vs 54% LIMITATION: + study for 60 min PR: 14% vs 24% Only 1 patient dose < (NOT met criteria for 100 Gy SIGNIFICANT) adequate HT t/t Head & 35 40 CR: 62 % vs 52 % LED to RTOG Neck PR: 10% vs 37 % guidelines for HT 45% LC: 43 % vs 37 % Pelvis 37 38 CR: 60 % vs 57% 40% PR: 10 % vs 8 %
- 36. Sugimachi single institutetrial (ESOPHAGUS) CRT HT RT HYPERTHERMIA End point n + No. Thermal CCT of # dose goal + RT n Esophagus 34 32 30 gy/15#/ Bleomycin & HT given Downstaging effect of 66 @ 2gy/# concurrently 1 hr prior to RT Neoadjuvant therapy 3 weekly Effective in 69% vs 44% p 6 Goal: 42.5 – 44 C Pcr : every 30 min 26% VS 8% P OS: 50 % vs 24% at 3 yrs Esophagus CCT CCT 6 Goal: 42.5 – 44 C Pcr : 40 alone + HT every 30 min 41 % VS 19 % P
- 37. Overgaard multicentric trial(MALIGNANT MELANOMA) HT RT HYPERTHERMIA End point Effect of heating RT + No. Thermal quality n RT of # dose goal n Melanoma 65 63 24 – 27 Gy 3 43 C for 60 min CR: 62% vs 35% p LIMITATION: 128 /3# @ at 3 mths Only 14% patients 8 – 9 Gy/# LC : 46% vs 28% p achieved the goal at 2 yrs of HT RR : RT+HT vs RT alone CR = 4.01 2 yr LC = 1.73
- 38. Sneed single institutetrial (GBM) Univ of California San Fransisco study BT ITHT BT HYPERTHERMIA End point Effect of heating boost + No. Thermal quality n BT of # dose goal n GBM 33 35 59.4 Gy 2 median range TTP median: 8 patients After /33# @ CME 43C 14.1 49 wk vs 33 wk p received only 1 HT RT 1.8 Gy/# t/t 68 60 Gy @ median range TTLTP : Grade 3 Toxicity: 0.4-0.6 CME 43C 57 wk vs 35 wk p 7 patients vs 1 Gy/hr T 50: 74.6 I -125 in 2 yr OS: But no good 100 hrs 31% vs 15% thermal dose relationship found Median survival: 85 wks vs 76 wks
- 39. Vander zee phaseIII trial DUTCH STUDY 1990 (PELVIS) - Previously untreated LA pelvic tumors RT HT RT HYPERTHERMIA End point Effect of heating n + No. Thermal quality RT of # dose goal n 361 176 182 1/wk ,upto 5 CR: 55% vs 39% 41% patients Target = 60 min after any at 3 mths received fewer point in tumor is 43 C OS: 30% vs 24% than 5 HT t/ts due at 3 yrs to refusal Cervix 56 58 46-50 Gy @ 1.8-2 Gy/# + BT boost CR: 83% vs 57% p Max benefit seen 114 LC: 61 % vs 41 %P among pelvic OS: 51 % vs 27%P tumors Rectum 71 72 46-50 Gy @ 1.8-2.3 Gy/# + 10 -12 Gy CR: 21% vs 15% 143 boost LC: 38% vs 26% p OS: 13% vs 22% Bladder 49 52 66-70 Gy @ 2 Gy/# CR: 73% vs 51% p 101 LC: 42 % vs 33 % OS: 28 % vs 22% Limitation: control arm RT alone received suboptimal therapy (no cct)
- 40. Sharma et alRandomized clinical study PGI STUDY 1986 (CERVIX) RT HT RT HYPERTHERMIA End point n + No. Thermal of # RT dose goal n CA 25 25 45 Gy / thrice a Goal: temp LC: 70 % vs 50% p CERVIX 20#/4 wks week raised to 42-43 C (II & III) @ 2.25 Gy/# over 15 min & No survival advantage + maintained over seen ICA with Cs next 30 min 137 followed by RT Toxicity: application after 30 min Only minor , tolerable (35 Gy to pt & manageable, not A) 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 1. 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
- 44. WHY HT STILLIN 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
- 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.
- 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
Editor's Notes
- #3 Hyperthermia kills cells in a log-linear fashion depending on the time at a defined temperature (Fig. 28.1A). Resulting survival curves typically have an initial shoulder region, followed by an exponential portion. The initial shoulder region indicates that damage has to accumulate to a certain level before cells begin to die. This is somewhat analogous to the sublethal damage that is seen with ionizing radiation, except that the shoulder region may not return to the same level for a subsequent heat fraction, depending on whether thermotolerance (heat-induced thermal resistance, as described in more detail below) is induced and still present from the initial heat fraction. At lower temperatures, a resistant tail may appear at the end of the heating period. This resistant tail is not a resistant subpopulation, as might be seen for radiation therapy when there is a hypoxic subfraction.The appearance of the resistant tail is also due to the induction of thermotolerance, which develops during the heating period. At temperatures above 43°C the tail does not develop, because temperatures in this range are nonpermissive for development of thermotolerance during heating.
- #4 point at which the slope changes = break pointAbove breakpoint : change in temp of 1°C = rate of cell killing doubled. Below breakpoint : rate of cell killing drops by a factor of 4 to 8 for every drop in temp of 1°C. (due to thermotolerance during heating)CEM (thermal isoeffect dose) used to asseess efficacy of heating
- #5 Limitations of CEM:Tumor temp varies during t/tConcept relates only to cell killing by heat , & doesn’t take into account radiosensitizationMin tumor temp T90 : temp exceeded by 90% of measured intratumoral points
- #7 Thermotolerance is equivalent in function to resistance of cells to radiation ( by repair & by S PHASE cells)2 ways by which tt develops?At low temp 39 – 42 c --- tt develops during heating after 2-3 hrs of exposureAbove 43 c --- but not during heating. Tt develops some time after heating has been stoppedIn normal tissues, it may take 1-2 weeks for tt to decay
- #8 because of the problems with cooling induced by increased blood flow, there is no reliable way to heat tumors uniformly to temperatures above 43°C, even for a short period of time. As was discussed above in the section on modifiers of thermal isoeffect dose, induction of step down heating is not likely to have a large effect on CEM 43°C, so efforts to deliberately induce it are probably not worth the effort.
- #11 bcoz perfusion is the primary mechanism for conducting heat.1) acute acidification (decreasing ph) a) induction of hyperglycemia - increased glycolysis and lactic acid production - reduce blood flow by increasing blood viscosity. b) glucose combined with the resp inhibitor MIBG (meta iodo benzyl guanidine), selectively drive down tumor intracellular pH c) pharmacologic agents that block the extrusion of hydrogen ions from cells, 2) decreasing tumor blood flow blood perfusion major impediment to effective heating SO, Temp in tumor increased if tumor blood flow decreased by vasoactive agent a) hydralazine b) nitroprusside c) angiotensin II d) nitric oxide synthase inhibitors (L-NAME) risk of hypotension 3) HYPOXIA IS ALSO EFFECTIVE RADIOSENSITIZER
- #12 NI RADIATION Can be administered using – - Noninvasive source – using externally applied power - Invasive sources –– direct application into tissue or for intracavitary use : include hot water tubes RF antennas RF electrodes ferromagnetic metals US transducers
- #15 Mech:Microwave guide : energy is coupled into tissue through temp controlleddeionized water bolus to maintain skin temp below 43 CMagnetic induction: this heating utilizes time varying magnetic fields to induce eddy currents into conductive tissueCapacitative heating: uses RF fields b/w 5 – 30 Mhz with ion currents being driven b/w 2 or more conductive electrodes heating gets concentrated at electrodes but saline bolus can be temp controlled to prevent hot spots on skin surface & help to cool supf fat varying electrode size can shift current distribution towards smallest of the electrodesegintracavitary esophagus
- #16 Radiofrequency phased arrayANTENNAS ARE DRIVEN IN PHASE LEADING TO PHASE ADDITION IN THE CENTRE OF TV. COUPLING OF ENERGY TO BODY ACHIEVED USING WATER FILLED BOLUSAdv : more deeper energy deposition
- #17 mech:Energy is coupled from us transducer having frequency of 1-3 mhz into the superficial tumor using degassed water.For deep heating , us frequency of 0.5-2 mhz is reqdLimitations:1) Anatomic geometry & tissue heterogeneity : Air reflects & bone preferentially absorbs2) Inadequate acoustic window : path unobstructed by bone & air prox & distal to target
- #19 - Direct contact between the metal electrodes and tissue required, but insulation can be used to prevent heating along selected regions of the electrodes (e.g., at the skin puncture site).Limitation: This technique suffers from the concentration of current density around the electrodes, thus requiring close electrode spacing (1 to 1.5 cm) and regular geometry. Heating near electrodes often causes treatment-limiting pain. Electrode cooling with air or water is advantageous but has not been routinely employed. Heterogeneous tissue conductivity or nonparallel electrodes can further compromise temperature uniformity
- #20 EM wavelength in tissue is on the order of a few centimetres the length of a single implanted electrode : equal to the EM wavelength so it is not an equipotential surface and heating is intrinsically nonuniform along its lengthinsulation has little effect because in this frequency range, current induction is predominantly capacitive (due to molecular polarization) instead of conductive (due to free ion drift).
- #22 Currently temp changes are monitored by measuring water proton resonance frequency shift(PRFS).Mri measuring the chemical shift of water can yield a 0.5 C resolution in 0.02 cm3 voxels in both normal & malignant tissues.OTHER non invasive tech are:US thermographyMicrowave thermographyEPR (electron paramagnetic resonance) much cheaper than MRI
- #23 Hypoxic cells are known to be three times more resistant to radiation, as compared with aerobic cells.
- #24 analogous to dose-modifying factor for any adjuvant to radiation
- #27 Why repair occurs? Radiation doesn’t damage differentiating cells, so when fractionation done, repair time is the time of natural life time of mature differentiating cells & time taken by stem cells to progress through process of differentiation & become functional
- #29 Platinum given simultaneously with HT ----= TISSUE extraction rate of drug increased with HT 5 FU contious infusion with HT ----= 1. ENHANCED CONVERSION TO ACTIVE METABOLITES hence increased cell killing 2. cell cycle block in S phase ----SENSITIVE PHASE For HT
- #30 Albumin extravasates from these vessels at normothermia, but heating at 42°C increases the rate by 25%. Drugs can be loaded into liposomes at high concentration..
- #32 Patients were randomized to RT alone & RT + HT gpt/t prescribed acc to RTOG/ESHO guidelinesHT tech somewhat differentGreatest benefit : Recurrent lesions in previously irradiated areasWhere further RT was of necessity, limited to low doses
- #40 2 folllow up phase III studies are going on:US led trial : best conventional therapy vs HT + CONV T/TDUTCH TRIAL: RT + HT vs RT + HT + CCT
- #44 Thermometry requires physicists time to place thermometry catheters, imaging to document thermometry placementPower application reqires skillNONINVASIVE thermometry : lead technology is MRI compatible RF phased arrays for HT treatment (being tested by Duke univ medical centre & charite hospital in berlin, germany)The success of crt protocols in incresinglrc has neglected the need of HT for achieving the same