HYPERTHERMIA, 한국의학물리학회에 바란다. 영남대학교 의과대학 방사선종양학교실 김 명 세 영남대학교 의과대학 방사선종양학교실 김 명 세

회원 여러분, 환영 합니다.

감사 드립니다. 회장님, 회원 여러분 ! 회장님, 회원 여러분 ! 귀중한 시간. 귀중한 시간. 회장님, 회원 여러분 ! 회장님, 회원 여러분 ! 귀중한 시간. 귀중한 시간.

2000 년 ICHO 세계온열종양학회 - 의학물리학회 협조 - 성공적인 학회 개최 가능 년 ICHO 세계온열종양학회 - 의학물리학회 협조 - 성공적인 학회 개최 가능.

HYPERTHERMIAHYPERTHERMIA Elevation of temperature to supraphysiologic level, between 40ºC-45ºC 45ºC  : Thermal ablation Elevation of temperature to supraphysiologic level, between 40ºC-45ºC 45ºC  : Thermal ablation

HYPERTHERMIAHYPERTHERMIA BIOLOGIC RATIONALEBIOLOGIC RATIONALE 1. Direct cytotoxicity 1. Direct cytotoxicity 2. Radiosensitizer 2. Radiosensitizer 3. Chemosensitizer 3. Chemosensitizer 4. Gene therapy 4. Gene therapy 5. Protein denature 5. Protein denature BIOLOGIC RATIONALEBIOLOGIC RATIONALE 1. Direct cytotoxicity 1. Direct cytotoxicity 2. Radiosensitizer 2. Radiosensitizer 3. Chemosensitizer 3. Chemosensitizer 4. Gene therapy 4. Gene therapy 5. Protein denature 5. Protein denature

HYPERTHERMIAHYPERTHERMIA Direct cytotoxicity ºC  : cell die exponentially (breakpoint) - Rate of killing: increase with temperature (1ºC  : doubles the rate of cell killing) (Gunderson & Tepper, clinical Radiation Oncology, 385p, 2007) Direct cytotoxicity ºC  : cell die exponentially (breakpoint) - Rate of killing: increase with temperature (1ºC  : doubles the rate of cell killing) (Gunderson & Tepper, clinical Radiation Oncology, 385p, 2007)

HYPERTHERMIA 2. Radiosensitizer - -Inhibits potentially lethal & sublethal damage repair. - -DNA repair process: heat sensitive. : No repair of chromosomal aberration by radiation. 2. Radiosensitizer - -Inhibits potentially lethal & sublethal damage repair. - -DNA repair process: heat sensitive. : No repair of chromosomal aberration by radiation.

HYPERTHERMIA 2. Radiosensitizer Reoxigenation in periphery  at 40ºC - 42ºC : Improve hypoxic, radiosensitive In tumor: vascular stasis - Arteriovenous shunting, thrombus formation. leucocyte plugging. - Vascular permeability  - edema . stasis . - Anaerobic metabolism  : Lactic acid , pH  : sensitive to HT, 2. Radiosensitizer Reoxigenation in periphery  at 40ºC - 42ºC : Improve hypoxic, radiosensitive In tumor: vascular stasis - Arteriovenous shunting, thrombus formation. leucocyte plugging. - Vascular permeability  - edema . stasis . - Anaerobic metabolism  : Lactic acid , pH  : sensitive to HT,

HYPERTHERMIA 3. Chemosensitizer Many chemotherapeutic agents: synergismMany chemotherapeutic agents: synergism with HT. with HT. MechanismMechanism 1) Increased cellular uptake 1) Increased cellular uptake 2) Increased oxygen radical production 2) Increased oxygen radical production 3) Increased DNA damage & inhibition 3) Increased DNA damage & inhibition of repair of repair 3. Chemosensitizer Many chemotherapeutic agents: synergismMany chemotherapeutic agents: synergism with HT. with HT. MechanismMechanism 1) Increased cellular uptake 1) Increased cellular uptake 2) Increased oxygen radical production 2) Increased oxygen radical production 3) Increased DNA damage & inhibition 3) Increased DNA damage & inhibition of repair of repair

HYPERTHERMIA 3. Chemosensitizer Chemotherapy agents: Loaded into liposomes (100 nm diameter) -HT augment liposome drug delivery. -Liposome: do not extravasate at normothermia, but do at 40-42ºC - even brain is sensitive 3. Chemosensitizer Chemotherapy agents: Loaded into liposomes (100 nm diameter) -HT augment liposome drug delivery. -Liposome: do not extravasate at normothermia, but do at 40-42ºC - even brain is sensitive

HYPERTHERMIA 3. Chemosensitizer Most chemotherapy: sensitive,Most chemotherapy: sensitive, esp. 5-FU: supraadditive with HT between esp. 5-FU: supraadditive with HT between 39-41ºC 39-41ºC 5FU: continuous infusion-Lead to cell cycle5FU: continuous infusion-Lead to cell cycle block in S phase, relatively sensitive part to block in S phase, relatively sensitive part to HT. HT. Reversal of drug resistance mechanismsReversal of drug resistance mechanisms Topoisomerase II activity  - activity of drug Topoisomerase II activity  - activity of drug  (>41.8ºC ) (>41.8ºC ) 3. Chemosensitizer Most chemotherapy: sensitive,Most chemotherapy: sensitive, esp. 5-FU: supraadditive with HT between esp. 5-FU: supraadditive with HT between 39-41ºC 39-41ºC 5FU: continuous infusion-Lead to cell cycle5FU: continuous infusion-Lead to cell cycle block in S phase, relatively sensitive part to block in S phase, relatively sensitive part to HT. HT. Reversal of drug resistance mechanismsReversal of drug resistance mechanisms Topoisomerase II activity  - activity of drug Topoisomerase II activity  - activity of drug  (>41.8ºC ) (>41.8ºC )

HYPERTHERMIA 4. Gene therapy Heat shock protein: potential role in regulating immune responses.Heat shock protein: potential role in regulating immune responses. 42ºC, 30min.: Several hundredfold induction of reporter protein expression under control of the HSP70 promotor.42ºC, 30min.: Several hundredfold induction of reporter protein expression under control of the HSP70 promotor. Improved tumor growth delay in B16 melanoma model.Improved tumor growth delay in B16 melanoma model. + RT: superior result+ RT: superior result 4. Gene therapy Heat shock protein: potential role in regulating immune responses.Heat shock protein: potential role in regulating immune responses. 42ºC, 30min.: Several hundredfold induction of reporter protein expression under control of the HSP70 promotor.42ºC, 30min.: Several hundredfold induction of reporter protein expression under control of the HSP70 promotor. Improved tumor growth delay in B16 melanoma model.Improved tumor growth delay in B16 melanoma model. + RT: superior result+ RT: superior result

HYPERTHERMIA 4. Gene therapy 4. Gene therapy *HT : effective in altering both adaptive & innate immunity. & innate immunity. * 40ºC  : could accelerate immune * 40ºC  : could accelerate immune reactivity. reactivity. 4. Gene therapy 4. Gene therapy *HT : effective in altering both adaptive & innate immunity. & innate immunity. * 40ºC  : could accelerate immune * 40ºC  : could accelerate immune reactivity. reactivity.

HYPERTHERMIA Protein denaturation : ≥ 40ºC - Apoptosis & necrosis. Protein denaturation : ≥ 40ºC - Apoptosis & necrosis.

HYPERTHERMIA In clinics In clinics Hyperthermia aloneHyperthermia alone : No long term tumor control : No long term tumor control - Widely practiced in alternative & - Widely practiced in alternative & complementary medicine complementary medicine HT + RTHT + RT - Clinical response rate: almost doubled - Clinical response rate: almost doubled in randomized &/or non randomized. in randomized &/or non randomized. In clinics In clinics Hyperthermia aloneHyperthermia alone : No long term tumor control : No long term tumor control - Widely practiced in alternative & - Widely practiced in alternative & complementary medicine complementary medicine HT + RTHT + RT - Clinical response rate: almost doubled - Clinical response rate: almost doubled in randomized &/or non randomized. in randomized &/or non randomized.

Rectal ca.

HYPERTHERMIA In clinics In clinics Trimodality with HT + RT + ChemoTX.Trimodality with HT + RT + ChemoTX. - Ongoing randomized trial - Ongoing randomized trial - Cervical cancer, colorectal cancer, - Cervical cancer, colorectal cancer, esophageal cancer, brain tumor, Head & esophageal cancer, brain tumor, Head & neck tumor, bladder tumor, pelvic tumor neck tumor, bladder tumor, pelvic tumor : Not finished, but favorable results. : Not finished, but favorable results. In clinics In clinics Trimodality with HT + RT + ChemoTX.Trimodality with HT + RT + ChemoTX. - Ongoing randomized trial - Ongoing randomized trial - Cervical cancer, colorectal cancer, - Cervical cancer, colorectal cancer, esophageal cancer, brain tumor, Head & esophageal cancer, brain tumor, Head & neck tumor, bladder tumor, pelvic tumor neck tumor, bladder tumor, pelvic tumor : Not finished, but favorable results. : Not finished, but favorable results.

HYPERTHERMIA In clinics In clinics In triple treatment(HT+RT+CT)In triple treatment(HT+RT+CT) - Almost 100% local control. - Almost 100% local control. No complication, except mild burn.No complication, except mild burn. -- Accident due to carelessness. -- Accident due to carelessness. In clinics In clinics In triple treatment(HT+RT+CT)In triple treatment(HT+RT+CT) - Almost 100% local control. - Almost 100% local control. No complication, except mild burn.No complication, except mild burn. -- Accident due to carelessness. -- Accident due to carelessness.

HYPERTHERMIA WHY NOT POPULAR? In Clinics Time consuming: about 1hr. for 1Tx. At least one doctor/ nurse/ technician should keep the patient. In many clinical trials: good results, but no real time confidence. WHY NOT POPULAR? In Clinics Time consuming: about 1hr. for 1Tx. At least one doctor/ nurse/ technician should keep the patient. In many clinical trials: good results, but no real time confidence.

HIFU ( High Intensity Focused Ultrasound)

HYPERTHERMIA WHY NOT POPULAR? In Physics In International J Hyperthermia (2007.2) 90%: Physics field. WHY NOT POPULAR? In Physics In International J Hyperthermia (2007.2) 90%: Physics field.

HYPERTHERMIA WHY NOT POPULAR? In Physics Homogenous temperature in target volumeHomogenous temperature in target volume Define temperature range precise and reproducible manner.Define temperature range precise and reproducible manner. Non invasive dosimetry xNon invasive dosimetry x Should be visible, easy applicationShould be visible, easy application WHY NOT POPULAR? In Physics Homogenous temperature in target volumeHomogenous temperature in target volume Define temperature range precise and reproducible manner.Define temperature range precise and reproducible manner. Non invasive dosimetry xNon invasive dosimetry x Should be visible, easy applicationShould be visible, easy application

PROBLEMS?PROBLEMS? Non invasive thermometry+ - still not use in most clinics Cancer Tx.: Surgery + RT + ChemoTx. - Overall survival: ~40% - Very expensive Complementary & Integrative Medicine ( 보완통합의학회 ) Non invasive thermometry+ - still not use in most clinics Cancer Tx.: Surgery + RT + ChemoTx. - Overall survival: ~40% - Very expensive Complementary & Integrative Medicine ( 보완통합의학회 )

보완통합의학 ? 대체의학 : 질병 치료에 효능이 있다고 주장하지만, 정통 서양의학의 관점에서 볼때 그 효능 을 입증할만한 객관적이고 과학적인 근 거가 부족한 치료법. ( 대한보완통합의학회지 4(1) S-19, 2007) ( 대한보완통합의학회지 4(1) S-19, 2007) 미국, 대체의학 비용 : 40-60% 의료보험비 지급 미국, 대체의학 비용 : 40-60% 의료보험비 지급 WHY NOT HYPERTHERMIA? 대체의학 : 질병 치료에 효능이 있다고 주장하지만, 정통 서양의학의 관점에서 볼때 그 효능 을 입증할만한 객관적이고 과학적인 근 거가 부족한 치료법. ( 대한보완통합의학회지 4(1) S-19, 2007) ( 대한보완통합의학회지 4(1) S-19, 2007) 미국, 대체의학 비용 : 40-60% 의료보험비 지급 미국, 대체의학 비용 : 40-60% 의료보험비 지급 WHY NOT HYPERTHERMIA?

HYPERTHERMIA *Even with the limitations of current technology, the promise of HT is emerging from the clinical trials. As the technology improves, the benefitsAs the technology improves, the benefits will only become more visible. will only become more visible. (Gunderson & Tepper. Clinical Radiation (Gunderson & Tepper. Clinical Radiation Oncology. 385p, 2007) Oncology. 385p, 2007) *Even with the limitations of current technology, the promise of HT is emerging from the clinical trials. As the technology improves, the benefitsAs the technology improves, the benefits will only become more visible. will only become more visible. (Gunderson & Tepper. Clinical Radiation (Gunderson & Tepper. Clinical Radiation Oncology. 385p, 2007) Oncology. 385p, 2007)

성공하는 사람들은 길에 눈이 쌓여도, 눈을 밟아가며 길을 나서지만, 실패하는 사람들은 눈이 녹기를 기다렸다가 길을 떠난다 성공하는 사람들은 길에 눈이 쌓여도, 눈을 밟아가며 길을 나서지만, 실패하는 사람들은 눈이 녹기를 기다렸다가 길을 떠난다

내겐 당신이 있습니다 ! 내 부족함을 채워주는 사람, 당신의 사랑이 쓰러진 나를 일으킵니다. 내게 용기, 위로, 소망을 주는 당신, 내가 나를 버려도 나를 포기하지 않는 당신, 나를 사랑하는 이가 이 세상에 존재 한다는것, 그것이 내 삶의 가장 커다란 힘입니다. 내겐 당신이 있습니다 ! 내 부족함을 채워주는 사람, 당신의 사랑이 쓰러진 나를 일으킵니다. 내게 용기, 위로, 소망을 주는 당신, 내가 나를 버려도 나를 포기하지 않는 당신, 나를 사랑하는 이가 이 세상에 존재 한다는것, 그것이 내 삶의 가장 커다란 힘입니다. 저의 힘이 되어주신 여러분, 다시 한번 감사 드립니다 ! 저의 힘이 되어주신 여러분, 다시 한번 감사 드립니다 !