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Hyperthermia and Radiotherapy 41 39 39 Hyperthermia and 37 Radiotherapy 37 A Study on Malignant Superficial Tumours Clas-Ebbe Lindholm Lund University Malmö 1992 From the Department of Oncology, Malmö Lund University Hyperthermia and Radiotherapy Oas-Ebbe Lindholm Malmö 1992 Doctoral dissertation Lund University Department of Oncology S-214 01 Malmö, SWEDEN © Clas-Ebbe Lindholm (page 1-104) ISBN 91-628-0525-8 CODEN:ISRN LUMEDW/(MEOK-1015) Printed in Sweden by Tryckeriet, Malmö allmänna sjukhus Organization uocumeni name i LUND UNIVERSITY DOCTORAL DISSERTATION Department of Oncology Dateofissue Apri| 4> m2 Lund University, Malmö Allmänna Sjukhus S-214 01 Malmö, Sweden CODEN: ISRN LUMEDW/(MEUK-1(m) Authors) Sponsoring organization Clas-Ebbe Lindholm Title and subtitle HYPLRTHERMIA and RAD'OTHERAPY- A study on malignant superficial tumours. Abstract Combined hyperthermia (HT 45 min once or twice per week) and low dose radiotherapy (LDRT 30-34.5 Gy in 2-3 weeks) have been given to 182 locally recurrent or metastatic superficial tumours in 133 patients. Tumour response was analysed in 137 tumours in 100 patients. The overall complete response (CR) was 50 % with a median duration (DCR) of 13±3 months. When mammary carcinoma, representing 62 % of the treated tumours, were analysed, CR was 62 % with a DCR of 14±4 months. In a comparative, non-randomized study, on 34 matched tumour pairs in 24 patients, treatment was given with LDRT+HT to the larger and the same LDRT to the smaller tumour, the patients acting as their own control. A significant difference in CR was obtained in favour of the combined treatment (p=0.0013 all diagnosis and p=0.0027 mammary carcinoma). There was no significant difference in DCR between the two modalities. However, approximately 30 % of the CR s in the combined treatment grouo ?but none in the LDRT alone group) were still in local CR when the patients died. No significant difference m CR was seen when tumours were randomly treated with HT once (CR 56 %) or twice (CR 69 %) per week combined with itie same LDRT. The DCR was 7±2 months and 14±4 months, respectively. This difference was not statistically significant. Predictive factors for CR, multivariately analysed (15 parameters), in mammary carcinoma recurring in earlier irradiated regions, were; the present LDRT absorbed dose (p=0.02) and the average minimum temperature in the best HT session (p=0.03). Significant skin toxicity was seen in 28 % of all the 182 heated regions. Prognostic factors for skin damage, multivariately analysed, were; the extension of the heated region (p=0.007) and the highest average maximum temperature in any of the HT sessions (p=0.04). Pain was in some way correlated to severe toxicity but was not considered to be an optimal monitor for HT 2S many patierts with severe and moderate pain were without any serious skin reactions, while slight or no pain sometimes were associated with severe reactions. Keywords Hypert ii-.-mia, Radiotherapy, Combined treatment, Comparat i VP study, Hatchet, pairs, Randomized study. Tumour response, Skin reactions, Pain, Predictinq factors. Classification system and/or index terms (if any) Supplementary bibliographical information Language 1 ni) 1 i sh ISSN and key title ISBN 9I_62H-()'J2S-0 Recipient's notes Number of pages Price Security classification Distribution by (name and address) I, the undersigned, being the copyright owner of the abstract of the above-mentioned dissertation, hereby grant to all reference sources permission^? publish and disseminate the abstract of the above-mentioned dissertation. Signature Date i ebruary 10, 1992 HyperthermJa and Radiotherapy A Study on Malignant Superficial Tumours by Clas-Ebbe Lindholm Med. lic, Lunds Nation Akademisk avhandling som för avläggande av doktorsexamen i medicinsk vetenskap vid medicinska fakulteten vid universitetet i Lund kommer att offentligen försvaras i patologiska institutionens föreläsningssal, Malmö Allmänna Sjukhus, lordagen den 4 april, 1992, kl. 9.00 (precis). Fakultetsopponent: Docent Bo Frankendahl, kliniken för gynekologisk onkologi, Radiumhemmet, Karolinska sjukhuset, 10401 Stockholm. fieoftte one ttieen ifatt eolct 1. Introduction 7 2. Aim of the Present Study 8 3. History 9 3.1. Observations of Heat Effects on Tumours in Man 9 3.2. Early Biological Considerations 10 3.3. Heat and Radiosensitization 11 4. Material, Methods and Results of the Study 13 4.1. The Whole Material 13 4.2. Controlled studies 13 4.2.1. Comparative, Non-randomized Study 14 4.2.2. Randomized Study 15 4.2.3. Pilot Study on General Anaesthesia During Heat 16 Treatment. 4.3. Papers IV 16 4.3.1. Paper I - Preliminary Results 16 4.3.2. Paper II - Comparative Studies 17 4.3.3. Paper III - Arterial Complications 18 4.3.4. Paper IV - Prognostic Factors, Tumour Response 19 4.3.5. Paper V - Prognostic Factors, Normal Tissue 20 Reactions 5. Discussion 22 5.1. Hyperthermia Alone 22 5.2. Hyperthermia Combined with Radiotherapy 22 5.2.1. Feasibility Studies. 22 5.2.2. Comparative Non-randomized Studies and 24 Matched-pair Analyses 5.2.3. Phase IH-trnls on the Effect of Radiotherapy Alone 27 Versus Radiotherapy Combined with Heat 5.2.4. Interstitial Heat Treatment Combined with 29 Radiotherapy 5.2.5. Predicting Factors of Tu.nour Response 30 5.2.5.1. Tumour Size 30 5.2.5.2. Tumour Histology, Diagnosis and Site of 32 Disease 5.2.5.3. Radiation Absorbed Dose 32 5.2.5.4. Thermal Factors 33 5.2.5.5. Thermal Dose 35 5.2.5.6. Sequence of Hypothermia in Relation to 36 Radiotherapy 5.2.6. Side Effects 37 5.2.6.1. Introductory Comments . 37 5.2.6.2. Cytotoxic Heat Effects 38 5.2.6.3. Radiosensitizing Toxicity 39 6. Conclusions 40 7. Comments for the Future 42 8. Appendices 44 8.1. Appendix 1: Biological and Physiological Background of 44 Hyperthermia 8.1.1. Hyperthermia Alone 44 8.1.1.1. Mechanisms of Cell-killing by Heat 44 8.1.1.2. Cells Sensitivity to Heat 46 8.1.1.3. Tissue Vascularization and its Effects on 49 Hyperthermic Treatment 8.1.1 A. Effects of Hyperthermia on Tissue 50 Vascularization 8.1.1.5. Tissue pH and its Relation to Heat Sensitivity 55 of Cells 8.1.1.6. Metabolic Effects of Heat 56 8.1.1.7. Thermotolerance 56 8.1.1.8. Step-up, Step-down Sensitization 59 8.1.2. Hyperthermia in Combination with Ionizing 60 Radiation 8.1.2.1. Introductory Comments 60 8.1.2.2. Radiosensitizing Effects of Heat 62 8.1.2.3. Heat, Radiation and Cell Cycle Phase 63 Sensitivity 8.1.2.4. Heat and OER of Ionizing Radiation 63 8.1.2.5. Time to Reach Response and Repair of 63 Combined Heat and Radiation 8.1.2.6. Thermal Enhancement, Therapeutic Gain and 64 the Importance of Sequence and Interval of the Treatment Modalities 8.1.2.7. Intrinsic Mechanism of Radiosensitization 66 8.1.2.8. Fractionated Heat and Ionizing Radiation 66 8.1.2.9. Final Conclusion on Fractionation of 67 Combined Heat and Radiation 8.2. Appendix 2: Physical Aspects 69 8.2.1. External Loco Regional Heating Techniques 69 8.2.1.1. Ultrasound Techniques 69 8.2.1.2. Electromagnetic Radio Frequency Field 70 Techniques in the Lower Range of ISM-frequencies 8.2.1.3. Radiative Electromagnetic Aperture techniques 71 8.2.2. Interstitial and Endocavitary Heating Techniques 73 8.2.2.1. Interstitial Radio Frequency Systems 74 8.2.2.2. Interstitial Microwave Techniques 74 8.2.2.3. Interstitial Hot Source techniques 75 8.2.2.4. Endocavitary Heating Technique 76 8.2.3. Thermometry 76 8.2.3.1. Introduction and Some Quality Assurance 76 Principles 8.2.3.2. Commercially Available Thermometer Probes 77 8.2.3.3. Non-invasive Thermometry 79 8.3. Appendix 3: Quality Assurance on the Thermometry 81 System 8.3.1. Introduction 81 8.3.2. Quality Assurance Performance 82 8.3.3. Quality Assurance Results 83 8.3.4. Conclusions on Quality Assurance 85 9. Acknowledgement 86 10. References 88 Preface This thesis is based on the following papers, which in the text will be referred to by their Roman numerals: I Microwave-induced hyperthermia and ionizing radiation. Preliminary clinical results. Clas-Ebbe Lindholm, Elisabeth Kjellén, Torsten Landberg, Per Nilsson, Bertil Persson. Acta Radiologica Oncology 21,241-254,1982. II Microwave-induced hyperthermia and radiotherapy in human superficial tumours; clinical results with a comparative study of combined treatment versus radiotherapy alone. Clas-Ebbe Lindholm, Elisabeth Kjellén, Per Nilsson, Sven Hertzman. International Journal of Hyperthermia, 3, 393-411,1987. III Arterial rupture after microwave-induced hyperthermia and radiotherapy. Clas-Ebbe Lindholm, Lars Andréasson, Tommy Knöös, Torsten Landberg, Otto Ljungberg. International Journal of Hypothermia, 6,499-509,1990. IV Low-dose radiotherapy in combination with hyperthermia in previously irradiated superficial recunent breast carcinomas. Elisabeth Kjellén, Per Nilsson, Clas-Ebbe Lindholm, Lars Weber. International Journal of Hyperthermia, submitted. V Acute skin reactions in patients with superficial recurrent mammary carcinomas treated with low-dose radiotherapy and hyperthermia. Per Nilsson, Elisabeth Kjellén, Clas-Ebbe Lindholm and Sally Hill. International Journal of Hyperthermia, to be submitted. Preliminary reports (proceedings) have been given at the following international meetings: i Microwave-induced hyperthermia and radiotherap. Clinical results. Clas-Ebbe Lindholm, Elisabeth Kjellén, Torsten Landberg and Sven Hertzman. In: Hyperthermic Oncology vol 1 1984, Ed. Overgaard J, Taylor and Francis, London and Philadelphia, Proceedings of the 4th International Symposium on Hyperthermic Oncology, 2 - 6 July, 1984, Aarhus, Denmark, pp 341-344. ii Comparative study of microwave-induced hyperthermia and/or radiotherapy in matched human malignant superficial tumours. Bertil Persson, Elisabeth Kjellén, Per Nilsson, Clas-Ebbe Lindholm and Torsten Landberg.
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