Hyperthermia in radiotherapy

Hyperthermia in radiotherapy

1. HYPERTHERMIA IN RADIOTHERAPY PRESENTER : DR.MOUMITA PAUL 1st Year PGT MODERATOR : DR.RUBU SUNKU ASSISTANT PROFESSOR DEPT. OF RADIATION ONCOLOGY BBCI

2. DEFINITION Elevation of temperature to a supra-physiologic level in the range of 39⁰C to 45⁰C.

3. HISTORY Ancient references to the specific use of hyperthermia (or induced elevation of temperature above normal either locally, in part of the body, or of the whole individual) are found within the medical history of cultures from around the world. Since the 17 th century there have been numerous reports of tumour regressions in patients suffering from infectious fever. In 1866, W.Busch , described that sarcoma of face disappeared with prolonged infection with Erysipelas. Westermark in 1898 deliberately used hyprthermia to treat cancer when he used water-circulating cisterns to treat inoperable carcinomas of the uterus with temperatures of 42-44⁰C.

4. Rationale Hyperthermia causes direct cytotoxicity and also acts as a radio-sensitizer. Mechanism of action is complementary to the effects of RT. Hyperthermia has effects on blood flow and tumor physiology.

5. Effects of Hyperthermia on Cell Survival Cause direct cytotoxicity Kills cells in an exponential manner and the rate of killing increase with temperature when heated to a sufficient temperature and for long enough duration. Initial shoulder region present. At lower temperatures, resistant tail at the end of heating period due to thermotolerence .

6. Cellular response to heat

7. The Arrhenius Relationship Defines temperature dependence on rate of cell killing by heat. The log slope of the HT survival curve (1/D₀) is plotted as a function of reciprocal of the absolute temperature(T). Biphasic curve It’s slope gives the activation energy of the chemical process involved in cell killing. Breakpoint : For human cells ,about 43⁰C.

8. The Arrhenius Relationship Significance : Above breakpoint : Temperature change of 1⁰C doubles the rate of cell killing. Below breakpoint : For every drop in temperature of 1⁰C , the rate of cell killing drops by a factor of 2 to 4. Basis for thermal dosimetry in clinical HT applications( as the slopes of Arrhenius plots derived from many in vitro and in vivo studies are nearly identical which provided long standing usefulness of this analysis).

9. The Arrhenius Relationship This analysis led to the hypothesis that target for cell killing is cellular proteins. Heat of inactivation for cell killing and thermal damage is similar to protein denaturation (130-170 kcal/mol).

10. Mechanisms of Hyperthermic Cytotoxicity Cellular and tissue response Primary target : Proteins (Cell membrane, cytoskeleton, nucleolus) Cell killing by protein denaturation : heat of inactivation 130-170 kcal/mol Ultimate cell death : by apoptosis or necrosis.

11. Predominant target molecule is protein. The cytoskeleton of cells is heat sensitive. Enzymes in the respiratory chain are more heat sensitive than enzymes in the glycolytic pathway. The heat sensitivity of centriole leads to chromosomal aberrations. Many DNA repair proteins are heat sensitive. In an organized tissues heat damage occurs more rapidly than radiation damage, because both differentiated and dividing cells are killed. Heat radio-sensitization is due to DNA damage and inhibition of its repair. The role of heat is to block the repair of radiation-induced lesions.

12. Effects of Hyperthermia

13. Mechanisms of Hyperthermic Cytotoxicity 2) Physiological response

14. Thermal Enhancement Ratio(TER) TER is defined as the ratio of the doses of X-rays required to produce a given level of biological damage with radiation dose alone to that for combination of radiation and heat. TER = ratio of doses with RT alone / RT+HT to achieve issoeffect TER increases with increasing temperature , upto a value of about 2 for a 1-hour heat treatment at 43⁰C. Typical TER values : 1.4 at 41⁰C, 2.7 at 42.5⁰C and 4.3 at 43⁰C. In canine oral squamous cell carcinomas,it was estimated to be approximately 1.15 , when HT was administered twice a week during a course of fractionated RT.

15. Thermotolerance Also known as thermal resistance, is the transient adapatation to thermal stress that renders surviving heated cells more resistant to additional stress. May take few hours to a week to decay. Mechanisms: Repair of protein damage via heat shock proteins(HSP) 70-90 kd (HSP has been proposed to be the mediators of thermotolerance in humans). 2 ways of thermotolerance development : At low temp.39-42⁰C – during heating period after an exposure of 2-3 hrs and above 43⁰C—after heating stopped. 1 st heat dose kills a substantial fraction of cells but daily treatment becomes less effective because of thermotolerance .

16. Thermotolerance Modifiers of the thermotolerance response : Thermal exposure above 43⁰C : Thermotolerance during the heating period is prevented. Step down heating : -- It is an initial short heat shock above 43⁰C, followed by a drop in temperature below this threshold, delays Thermotolerance . -- Difficult to achieve clinically Acute reduction in pH, delays thermotolerance . --Acute acidification is brought about by- induction of hyperglycemia glucose combined with respiratory inhibitors MIBG (meta iodo benzyl guanidine) pharmacological agents that block the extrusion of hydrogen ions from cells.

17. Thermal Dose Sapareto and Dewey proposed the concept of “Cumulative Equivalent Minutes” (CEM). Normalise thermal data from hyperthermia treatments using this relationship CEM 43⁰C = t R˄(43-T) Where CEM 43⁰C is the cumulative equivalent minutes at 43⁰C(the temp.suggested for normalisation ) t is the time of treatment T is the average temperature during desired interval of heating R is a constant. (Above breakpoint R=0.5 and below 0.25) For complex time-temperature history, heating profile is broken into intervals of time “t” length, where the temperature remains relatively constant. CEM 43⁰C = Σ t R˄(43-Tavg)

18. Immunological effect of HT: Enhanced immunogenicity and HSP expression. Increased T-cell, NK cell and dendritic cell maturation and activity. Enhanced trafficking of immune effector cells into tumors. (mediated by cytokines such as interleukin 6)

19. Factors affecting response to HT Temperature Duration of heating Rate of heating Temporal fluctuation in temperature Spatial distribution of temperature Environmental factors (pH and nutrient levels) Combination with radiotherapy, chemotherapy, immunotherapy, etc. Intrinsic sensitivity

20. Rationale for combining RT+HT Cell in late S phase of cell cycle and hypoxic cells are radioresistant but are most sensitive to hyperthermia. Hyperthermia can lead to reoxygenation which improves radiation response( Radiosensitisation ). Inhibits the repair of sub-lethal and potentially lethal damage.

21. HT in Chemotherapy Mechanisms: 1.Increased cellular uptake of drug 2. Increased oxygen radical production 3. Increased DNA damage and inhibition of repair Eg.including Cisplatin and related compounds,melphalan , cyclophosphamide , nitrogen mustards, anthracyclines , nitrosoureas , bleomycin , mitomycin C, and hypoxic cell sensitisers .

22. Modalities of Hyperthermia 1)Superficial RT 2)Deep/Regional HT 3)Interstitial RT 4)Whole body RT

23. Methods of Heating Electromagnetic heating Ultrasound heating Interstitial hyperthermia Thermal conduction

24. Problems in delivery of clinical hyperthermia: Irregularities of patient anatomy and tissue interfaces Blood perfusion which varies among tissue types and function of time and local temperature. Continuous monitoring during treatment to readjust the heating pattern for uniform temp. as blood flow changes rapidly.

25. ELECTROMAGNETIC HEATING Mechanism : Electric field passes through material : resistant heating occurs Focus of heating broad : with low frequency and high wavelength Can be invasive or non invasive superficial heating deep heating 1.Superficial heating-effective penetration of 2 to 5 cm. 1.Deep heating- penetration >5 cm 2.Operate in microwave band at 433, 915 and 2450 MHz. 2.Use lower EM frequencies in the RF band 5 to 200 MHz 3.Waveguides, microstrip or patch antennas 3.Three techniques- Magnetic induction Capacitive coupling Phased array fields

26. Superficial Heating The frequency of microwave hyperthermia used are 430 MHz, 915 MHz and 2450 MHz. Rectangular or circular metal structure that guides EM waves from a single monopole.

27. BSD 2000 Sigma (deep heat system)

28. BSD-2000/3D Designed particularly for treating tumours in hard-to-reach locations. The targeted treatment area is enclosed by an eye-shaped applicator. Phase and amplitude steering is used to create the heating focus within the applicator. The 3D technology uses 24 dipole antennas of the Sigma Eye driven by 12 RF power channels to optimise the targeted heating. The 24 dipoles are arranged in three rings of 8 antennas each. By varying the phase and the amplitude of each of the 12 input channels, the operator can enhance the heating in the tumour and reduce the heating in non-target tissues.

29. Thermotron RF-8;

30. Thermotron RF-8 It uses electromagnetic waves to reach tumour tissue wherever it is located in the body. It works by heating a region of the body between a pair of parallel-opposed circular electrodes. Possible to selectively heat regions of different depth by using combination of large and small electrodes. Deep seated tumours can be heated uniformly. Presence of self-excited oscillator that is used to adapt the fluctuation of the specific frequency of the target lesion.

31. Ultrasound Heating Mechanism: Acoustic field transfer energy with viscous friction. Penetration of US field decreases with increasing frequency. But,anatomic geometry and tissue heterogeneity (air reflects,bone preferentially absorbs) severely limit the utility of US. Useful in intact breast and non bony soft tissue sites. Include single transducer and multiple transducer devices for superficial tumours (2-5cm)heating. Operate in 1-3 MHz range.

32. Ultrasound Heating Coupled into tissue using a water bolus which is temperature controlled. Bolus water is degassed since US cannot propagate in air.(i.e., air has to be removed) Good surface contact achieved by using a coupling gel.

33. Interstitial Hyperthermia Principle: Usually combined with brachytherapy : double use of the implant for both HT and RT. Ways: Simultaneous delivery 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 Lost its popularity due to decline in brachytherapy use and non-uniform distributions.

34. Thermal conduction: Simplest method of heating; e.g. hot water baths, circulating hot water in a needle, a catheter or a surface pad. Limitations: The tumor may not be at the same temp. as the skin (in case of hot water baths). Limited penetration of heat from a hot source. Restricted to interstitial applications.

35. Whole Body RT A technique to heat whole body either up to 41-42°C for 60 minutes (extreme WBHT) or only 39.5-41°C for longer time, e.g.3 hours (Moderate WBHT). In carcinomas with distant metastasis, a steady state of maximum temperatures of 42°C can be maintained for 1 hour with acceptable adverse effects. Intended for activation of drugs or enhancement of immunologic response.

36. Isolated Limb Perfusion Hyperthermic Limb perfusion involves isolation of the limb from systemic circulation. CT is administered often in the range of 60 mins with extracorporeal circulation. At the beginning of perfusion phase , the blood in the limb is heated after which CT infusion begins. High concentration of CT can be delivered to the targetted limb while minimising cytotoxicity.

37. Hyperthermic Intraperitoneal Chemoperfusion (HIPEC ) Hyperthermia therapy used in combination with surgery in treatment of advanced abdominal cancers. Used for treating cancers that have spread to the lining of abdominal cavity(Ca appendix, Ca colon, Ca stomach and Ca ovaries). Delivers CT directly to cancer cells unlike systemic CT. After debulking /macroscopic tumour removal, the abdominal cavity is rinsed with a heated chemotherapy solution(usually approx.at 40⁰C). Heat potentiates the effect of CT by reducing tumour cell resistance. Mitomycin -C and Oxaliplatin for colorectal cancer, amd Cisplatin for ovarian cancer. Decreases systemic side effects.

38. Hyperthermic Intraperitoneal Chemoperfusion (HIPEC )

39. Trials on HIPEC Phase III trial by Willemian J.van Driel et al. (The New England Journal of Medicine) to see the overall survival and the side effect profile of patients in stage III epithelial Ovarian cancer.245 patients were randomly assigned who had atleast stable disease after 3 cycles of carboplatin and paclitaxel to undergo cytoreductive surgery either with or without administration of HIPEC with cisplatin Results: The median overall survival was 33.9 months in the surgery group and 45.7 months in the surgery+HIPEC group.The percentage of patients who had adverse events of grade 3 or 4 was similar in the two groups.

40. Randomized Trial: Cytoreduction and Hyperthermic Intraperitoneal Chemotherapy Versus Systemic Chemotherapy in Patients with Peritoneal Carcinomatosis of Colorectal Cancer The median progression-free survival was 7.7 months in the control arm and 12.6 months in the HIPEC arm ( P  = 0.020). The median disease-specific survival was 12.6 months in the control arm and 22.2 months in the HIPEC arm ( P  = 0.028). The 5-year survival was 45% for those patients in whom a R1 resection was achieved.

41. Thermometry Thermometry : procedure to measure intra- tumoral temperature For superficial tumours (0.5 cm) : probes attached on skin surface or mapped through catheters lying on skin For deep tumours : Invasive thermometry is standard. Angiocatheter inserted in tumour at a point, perpendicular to the direction of electric flow. Temp.is measured by putting a thermocouple probe in angiocatheter Record : lowest thermal dose (lowest temp*time) highest 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 magnetisation , resonance frequency of water atoms.

42. Hyperthermia Toxicity HT toxicities (studies) with or without radiation is minor only. Doesn’t result in treatment interruption. Thermal burns-generally grade I Pain Systemic stress

43. CR rates were 39% after RT alone and 55% after RT+HT. The duration of local control was significantly longer with RT+HT than RT alone. For cervical cancer, for which the CR rate with RT+HT was 83% compared with 57% after Rt alone.

44. At 12 year follow-up, local control remained better in RT+HT group(37% vs 56%). Survival was persistently better after 12 years : 20%(RT) and 37%(RT+HT) Hyperthermia did not significantly add to radiation-induced toxicity compared with RT alone. Study by Franckena et al; IJROBP 2008

45. Trials(Phase III) showing compatibility of RT alone VS RT+HT In general, clinical response rates with the addition of HT to RT have approx.doubled from 25-35% with RT alone to 50-70%.

46. Chemotherapy Trials The Rotterdam group treated 19 patients with locally recurrent Ca cervix post RT with a combination of HT and Cisplatin (overall response rate was 53% with 1 complete response). Another phase I/II trial by Hilderbrandt et al, in which nine patients with locally advanced rectal carcinoma having failed RT with/without surgery were treated with CT( oxaliplatin , folinic acid and 5-FU) in combination with HT, was well tolerated and quite feasible.

47. Trimodality Therapy Trials The combination of CT, RT, and HT was explored in an international collaborative study for locally advanced cervical carcinoma. [ 68 patients, all patient received 45-50Gy WP-RT followed by brachytherapy boost with a total dose to point A- 86Gy with weekly concurrent cisplatin , external HT was delivered weekly.] The 2 year survival was 78% and DFS was 71%. Rau and colleagues from Berlin also explored the use of preoperative trimodality therapy for locally advanced untreated rectal carcinoma.(RT, HT, and 5-FU/ leucovorin ) [36 patients, RT to 45Gy with weekly HT] [32 patients were surgically resectable , 5 patients with CR] After surgery OS was 86% at 38 months with no local recurrence.

48. The use of trimodality therapy also reported for locally recurrent breast cancer. [23 patients were treated with superficial HT and RT to a dose of 45Gy and capecitabine CT in 21, vinorelbine in 2 and paclitaxel in 4 patients.] [ 23 of whom previously irradiated and 22 had received prior CT] 80% of patients achieved a CR with 76% locally controlled at 1 year.

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50. Meta-analysis Datta NR, et al. Int J Hyperthermia.2016 (Hyperthermia and radiotherapy in the management of head and neck cancers : A systematic review and meta-analysis) A total of 498 abstracts were screened from four databases and hand searched as per the PRISMA guidelines.CR was evaluated in patients of head and neck cancers treated with either RT alone, or RT+HT without concurrent CT or surgery. Results : Overall CR with RT alone was 39.6% whereas with RT+HT it was 62.5%. Acute and late grade III/IV toxicities were reported to be similar in both the groups.

51. Meta-analysis Datta NR, et al. Int J Radiat Oncol Biol Phys.2016 (Hyperthermia and Radiation Therapy in Locoregional Recurrent Breast Cancers : A Systematic Review and Meta-analysis) CR was evaluated in patients of locally recurrent breast cancers.A total of 708 abstracts were screened from 8 databases according to PRISMA guidelines.Single arm and 2-arm studies, treating LRBCs with HT and RT but without surgery(for local recurrence) or concurrent chemotherapy were considered. Results: In the 2-arm studies, A CR of 60.2% was achieved with RT+HT vs 38.1% with RT alone.In 26 single arm studies, RT+HT attained a CR of 63.4%. A Cr of 66.6% was achieved with HT and re-irradiation in previously irradiated patients. Mean acute and late grade3/4 toxicities with RT+HT were 14.4% and 5.2% respectively.

52. Conclusion Hyperthermia is an useful adjuvant to radiotherapy and chemotherapy. Associated with increased local control rates with comparable acute side effects and no late toxicity. Major drawbacks: Cannot treat all sites;difficult for deep seated tumours Cannot deliver exact dose Non uniformity in doses Difficult/variable thermometry Difficult to set up and delivery in some positions Uncomfortable for patients

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