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丸暨
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1 Introduction of Radiotherapy cancer

2 cancer 癌症依其原發部位可分為約五十種 ( 台灣健保局分類 ) 每種部位均有其專門的治療方式 ; 同一部位的癌症依其疾病進展分為不同期別 ( 通常分四期, 第一二期屬早期, 第三四期屬晚期 ), 不同期別其治療方式亦有所不同適合的癌症治療, 首先就是要確定診斷 : 包括正確的部位及正確的期別, 這需要各個不同專門領域的醫學專科 ( 如內科外科外科病理科病理科影像醫學科影像醫學科核子醫學科等 ) 相互合作, 才能達成接著要依據診斷的部位及期別, 還有考量患者身體情形家屬的配合互動, 量身訂做一個最適合且完整的治療計畫, 這更是需要各個不同醫學專科之間的密切合作由於癌症的治療通常包含手術手術化學治療及放射線治療化學治療及放射線治療等三大部分, 所以至少需要外科醫師 ( 如一般外科耳鼻喉科婦產科等 ) 內科腫瘤科醫師及放射腫瘤科醫師共同討論

3 民國 92 年癌症登記報告行政院衛生署國民健康局

4 民國 92 年全癌症發生概述發生個案男性女性個案數 ( 人 ) 36,285 26,257 年齡中位數粗率 ( 每十萬人口 ) 年齡標準化率 ( 每十萬人口 ) 性別比 ( 年齡標準化率 ) 合計 62,542 註 : 年齡標準化率係使用 2000 年世界標準人口為標準人口

5 民國 92 年男女性十大癌症發生分率 (6,753 人 ) 肝 19% (5,025 人 ) 肺 14% (4,677 人 ) 結腸及直腸 13% (4,040 人 ) 口腔 11% (2,308 人 ) 胃 6% (2,237 人 ) 攝護腺 6% (1,318 人 ) 膀胱 4% (1,258 人 ) 食道 3% (1,157 人 ) 鼻咽 3% (960 人 ) 皮膚 3% (6,552 人 ) 其他癌症 18% 男性共 36,285 人 20% 乳房 (5,325 人 ) 14% 結腸及直腸 (3,561 人 ) 10% 肝 (2,651 人 ) 9% 肺 (2,390 人 ) 8% 子宮頸 (2,061 人 ) 5% 胃 (1,226 人 ) 4% 甲狀腺 (975 人 ) 3% 卵巢 (833 人 ) 3% 子宮體 (793 人 ) 3% 皮膚 (783 人 ) 22% 其他癌症 (5,659 人 ) 女性共 26,257 人備註 : 口腔癌含下咽及口咽

6 癌早期只局限於上皮細胞層, 並未侵入到周圍組織細胞時, 稱為原位癌民國 92 年與 91 年國人十大癌症發生率比較 ( 不含原位癌不含原位癌 ) 92 年 91 年 92 年與 91 年原發部位個案數粗發生率年齡標準年齡標準年齡標準化發化發生率化發生率生率增減 (%) 女性乳房 5, (1) % 肝及肝內膽管 9, % 結腸及直腸 8, % 肺支氣管及氣管 7, % 口腔口咽及下咽口咽及下咽 4, % 攝護腺 2, (2) % 子宮頸 2, (1) % 胃 3, % 膀胱 1, % 皮膚 1, % 其他部位 16, 總計 62, % (1) 每 10 萬女性人口 (2) 每 10 萬男性人口發生率..每 10 萬人口

7 原位癌 (carcinoma in situ) 係指上皮細胞癌最早期, 或定義為第 0 期的癌症通常上皮細胞癌 (carcinoma) 係指癌細胞從黏膜表層長出來, 例如胃腺癌大腸癌或泌尿道上皮細胞癌, 或是由皮膚表面長出來的根據組織學分類, 上皮細胞癌依據其外型及功能之不同, 又可分為扁平 ( 鱗狀 ) 上皮細胞癌 (squamous cell carcinoma) 以及腺癌 (adenocarcinoma) 兩大類, 如腫瘤係由腸胃道黏膜上皮長出者, 多為腺癌 ; 由皮膚表面, 或子宮頸長出者, 多為扁平上皮細胞癌, 由支氣管上皮長出之非小細胞肺癌, 它可以是扁平上皮細胞癌或腺癌, 而由泌尿道黏膜長出來者, 由於其組織型態特殊, 而有特別的名稱, 稱為移形上皮細胞癌 (transitional cell carcinoma)

8 原位癌 (carcinoma in situ) 如果癌細胞只有侷限在表層的黏膜層, 並未穿過基底膜, 則定義為原位癌, 包括子宮頸癌乳癌泌尿道移形上皮細胞癌的早期均可以是原位癌, 其診斷必須在顯微鏡下觀察由於原位癌並未穿過基底膜, 未深入黏膜下層 (sabserosa), 較不容易出現遠端轉移之情形, 經過適當治療 ( 通常是手術切除, 或合併放射線治療, 有很高的機會可以治癒, 應盡早就醫, 接受正規治療, 以免錯失治療的時機

9 民國 92 年主要癌症年齡標準化發生率之性別比例食道口腔 ( 含口咽及下咽 ) 鼻咽肝及肝內膽管膀胱肺支氣管及氣管胃結腸及直腸皮膚甲狀腺 0.32 全癌症性別比 ( 男 : 女 )

10 民國年男性十大癌症五年相對存活率部位別全癌症肝肺結直腸口腔胃攝護腺膀胱食道鼻咽皮膚一年二年三年四年五年民國年女性十大癌症五年相對存活率部位別全癌症乳房子宮頸結直腸肝肺胃甲狀腺皮膚子宮體卵巢一年二年三年四年五年

11 民國年男性十大癌症發生率五年變化圖食道癌口腔癌鼻咽癌結直腸癌攝護腺癌肝癌肺癌膀胱癌皮膚癌胃癌全癌症五年變化率 (%)

12 民國年女性十大癌症發生率五年變化圖子宮體癌乳癌 7.31 卵巢癌 4.38 結直腸癌 1.73 肝癌 1.72 肺癌甲狀腺癌胃癌皮膚癌子宮頸侵襲癌全癌症五年變化率 (%)

13 國人十大癌症發生之年齡中位數與個案數 ( 不含原位癌不含原位癌 ) 癌症部位年齡中位數個案數女性乳房 50 5,325 口腔口咽及下咽口咽及下咽 51 4,435 子宮頸 54 2,061 肝及肝內膽管 64 9,404 結腸及直腸 67 8,238 皮膚 69 1,743 膀胱 70 1,858 肺支氣管及氣管 70 7,415 胃 70 3,534 攝護腺 74 2,237

14 發生數民國年乳房原位癌與侵襲癌發生個案數圖 6,000 5,000 原位癌侵襲癌 4,437 4,619 4,784 4,879 5,325 4,000 3,575 3,764 3,052 3,000 2,792 2,238 2,368 2,464 2,000 1, 民國年

15 民國年口腔癌年齡標準化率之長期趨勢年齡標準化率 ( 每十萬人口 ) 男性發生率男性死亡率女性發生率女性死亡率發生年代註 : 年齡標準化率係使用 2000 年世界標準人口為標準人口

16 Introduction of Radiotherapy

17 內容大綱 Energy Absorption 定義輻射的種類輻射與物質的作用輻射對生物作用的機制 - 直接效應 - 間接效應中子對生物作用的機制比較光子和中子對生物作用的機制 RBE 與 LET 結論

18 Energy Absorption Consider 70 kg person LD 50/60 = 4 Gy (400 rad) Energy absorbed: 70 kg 4 J kg -1 = 280 J What is the caloric equivalent of 280 J? Calorie, metric unit of heat measurement. The small, or gram, calorie (cal) is the amount of heat required to raise the temperature of 1 g of water from 14.5 to 15.5 C. 1 cal equals joules (J) 280 J / = 67 calories What would be the temperature rise in the body from this energy deposition? Why is this a lethal dose?

19 定義廣義研究輻射線對生物或有機體的影響個體系統器官組織細胞分子皆涵蓋狹義主要針對游離輻射所造成的生物效應

20 游離輻射的種類本質上而言粒子射線 α β p n. 等電磁輻射電磁輻射 γ-ray X-ray. 等

21 游離輻射的種類游離輻射直接游離輻射 (direct ionizing radiation) α β p.. 等帶有電荷間接游離輻射 (indirect ionizing radiation) γ-ray X-ray n. 等不帶有電荷

22 輻射的種類作用上而言游離輻射 (ionizing radiation) α β p γ-ray X-ray n. 等非游離輻射 (nonionizing radiation) UV 無線電波紅外線. 等

23 游離輻射的種類

24 輻射與物質的作用從物理上來看 ~ 光電效應 (photoelectric effect) ~ 康普吞效應 (Comptom effect) ~ 成對發生 (pair production) 從生物上來看 ~ 游離作用 ~ 激發作用

25 Biological effects of radiation result principally from damage to DNA 輻射對生物分子的作用機制直接作用 (direct action) 指輻射對靶分子之直接打擊, 所造成之傷害間接作用 (indirect action) 指輻射經由介質或水產生之自由基 ( 游離基 ), 間接造成靶分子活性喪失而稱

26 Indirect Action in Detail H 2 O -> H 2 O + + e - H 2 O + is an ion (electrically charged) H 2 O + is also a free radical unpaired electron in outer shell very reactive H 2 O + H 2 O + -> H 3 O + + OH OH (hydroxyl radical)

27 中子對生物作用的機制

28 直接作用 (direct action) 細胞物質分子 : 蛋白質胺基酸上的支鏈斷裂或脫氫脂肪易形成自由基不飽和脂肪酸在有氧時形成過氧化酸 DNA 斷裂鹼基脫離改變等

29 間接作用 (indirect action) 輻射游離或激發細胞內的水分子而產生自由基或是 H 2 O 2 等中間產物這些中間產物化性活潑, 易與細胞重要分子起作用而造成傷害細胞中水分多, 間接作用比直接作用比例多

30 比較中子和光子的生物作用機制 X and g-rays indirectly ionizing produce fast moving secondary electrons Neutrons indirectly ionizing produce recoil protons, alphas, and heavier atoms

31 RBE (Relative Biological Effectiveness )

32 RBE 與 LET Low dose RBE LET(Linear Energy Transfer ) 任何離子沿其軌跡在每毫微米 (µm) 介質中所釋放出能量 (kev/ µm ) Energy,LET Mass,LET LET,RBE (LET<100 kev/ µm ) LET,RBE (LET>100 kev/ µm )

33 結論 X- and g-rays indirectly ionizing produce fast recoil electrons Neutrons are indirectly ionizing produce fast recoil protons, a-particles, Biological effects due to direct action indirect action about 2/3 of X-ray damage is by indirect action Photons - Indirect action dominates Heavy particles - direct action dominates

34 Basic Principles of Radiotherapy

35 The aims of radiation therapy Curative: with an intention to cure the tumor. First goal: local tumor control: Secondary goal: functional preservation Palliative: Not to cure the tumor (because patients disease is not curable by local treatment, To prolong patient's life or relieve their suffering, usually for patients with metastatic disease.

36 Curative RT First goal: local tumor control Cancer treatment failure 1/3 die of distant metastasis (DM) 1/3 die of local failure (LF). 1/3 die of both LF and DM. The price for LF Death!!! for most patients. Poor life quality and organ function If salvageable by further treatment, Could RT cure cancers? Eg.: tumors cured by RT alone 2/3 patients with uncontrolled local disease. Cervical cancer, stage I (non-bulky) >90%, II = 70-75%, III: 50%

37 Curative RT Secondary goal: functional preservation Cure tumor + acceptable (at least) organ function. Major sites: Eg: Early breast cancer, Vocal cord cancer, Hypopharyngeal cancer, Eye (melanoma), Anal cancer, Bladder, Prostate, Other sites Head and Neck tumor, Esophagus, Cervix, Uterus, Central nervous system, soft tissue sarcoma.

38 RT for benign disease: prevent progression or re-growing Eg: Meningoma, pituitary tumor, A- V malformation, Keloid and others

39 Palliative RT Aim Maintain life brain metastasis, super vena cava compression. Decrease suffering and improve life quality bone metastasis, spinal cord compression, Duration of palliation Short term : << doses needed to cure, << time for curative course Not bring significant suffering to patients who are expected to survive several months and usually not longer than a year. Long-term palliation: For incurable but slow disease progression. Dose is usually slightly lower than curative dose. Eg. Late relapse breast cancer,

40 Radiocurability Therapeutic ratio: The ratio of tumor control probability to normal tissue complication probability (TCP vs. NTCP). Increased therapeutic ratio means increased the ratio of TCP/NTCP. Sigmoid nature of TCP and NTCP TCP NTCP Dose

41 Precise tumor localization Dose dependent Basic Principles of RT Dose and volume dependent Tumor control Complications

42 Determining factor - Dose & volume RT dose Dose used in the clinics AA compromise between TCP and NTCP Tumor type dependent Intrinsic radiosensitiviity Volume-dependent

43 Intrinsic radiosensitivity of tumor Radiosensitive tumor lymphoma, leukemia, seminoma (a male testicular tumor), dysgemonia (a female ovary tumor), and some pediatric tumor. Radioresistent tumor eg. melanoma, soft tissue sarcoma, and malignant brain tumor. Individualized medicine in RT? Till now, no reliable methods were used in the clinics to predict individual tumor radiosensitivity and normal tissue radiosensitivity.

44 Dose- and volume- dependent Example: Squamous cell carcinoma of upper respiratory tract Subclinical disease for neck metastasis: cgy, 90% control. 1-3 cm: cgy, 90% control. 3-5 cm: cgy, 70% control.

45 Reduce dose to normal tissue - precision of tumor Define tumor extent Clinical examination, Imaging examination, Operation findings, Pathological findings, Natural cancer history,

46 Reduce dose to normal tissue - precision of tumor 精密度 Reproducibility and Precision: Good fixation device: reproducibility CT-treatment planning: define normal tissue and target.

47 Reduce dose to normal tissue - precision of tumor Conformity: Virtual simulation and beam s eye view 3-D conformal planning and IMRT

48 Reduce dose to normal tissue - precision of tumor Dosimetry Quality assurance

49 Revolution of external RT technique Old techniques (non-conformal therapy) 3-D conformal radiotherapy (3D-CRT) Intensity modulated radiotherapy (IMRT)

50 Equipments in a modern RT department Good immobilization device. Reproducible in the space. Imaging acquisition CT simulator, respiration gating, 4-D CT Networking system Treatment planning 3-D & IMRT Linear accelerator IMRT Electronic portal image Respiratory gating On board image for IGRT and cone beam CT Computer-controlled treatment. Calibration and dosimetry device.

51 How we do the daily practice Application of TDF ( Time, Dose and Fractionation in Radiotherapy

52 Historical observation Single dose: Sterilization skin damage Multiple smaller: Sterilization no skin damage

53 Clinical observation Strandquist plot A: skin necrosis, B: cure of skin carcinoma, C; moist desquamation. D: dry desquamation E; erythema

54 Ellis Nominal Standard Dose Total dose = (NSD)T 0.11 N 0.24 Weakness: 1. Time factor is not right. 2. Only consider acute responding tissues.

55 Acute vs. late responding tissues Acute responses: occurring during or within short time after RT. Such as mucositis, skin reaction, bowel responses,bone marrow depression. More related to total dose and time, less related to fraction size. Late responses: occurring months to years after RT. Such as fibrosis of tissue, radiation myelopathy, renal damage, usually are irreversible changes when damage is formed. More related to fraction size and total dose, less related to total time. The behaviors of tumor are more similar to those of acute responding tissues.

56 Time factor Compensation of time factor for acute responding tissue by extra dose

57 Animal model of acute vs. late responding tissues

58 Clinical model of acute vs. late responding tissue

59 Time factor: accelerated repopulation

60 Clinical evidence of accelerated repopulation Dose increase = 0.6 Gy/day

61 Clinical evidence of (accelerated) repopulation 1. Tumor regrowth in post-c/t or surgery. 2. Continuous Hyperfractionated Accelerated Radiation Therapy (CHART) (see following slides)

62 Q & A for time factor Q1: Will prolong total treatment time reduce late complications? A: No Q2: Will prolong total treatment increase the possibility of repopulation? A: Yes Q3: The total treatment time should be as short as possible, but what are the limitations? A: 急性副作用, 分次

63 Fractionation factor Question 1: 3 Gy/per fx. x 10 = 2 Gy/per fx. x 15 (????) Repeated shoulder A: Biological effects 30 Gy/10 fx > 30 Gy/15 fx

64 Fractionation factor Q2: Does fractionation scheme bring same effects to early- and late responding tissue A: see next slide Q: Does acute responding tissue have same doseresponse curve with the late responding tissues? A: No!!!

65 Expand the difference of early vs. late tissues by fractionation A: Fractionation protects late responding tissues damage than acute responding tissues

66 Dose-response for acute and late responding tissue Increasing total dose Decreasing fraction size Late responding tissues Acute responding tissues

67 How to evaluate the effects of fractionation on acute vs. late responding tissues? For example: 3 Gy x 10 fx. Vs. 2 Gy x 20 Gy Q: Do these treatment doses have same biological effects between acute and late responding tissues? A: No Q: Does any way to describe the differences between acute and late responding tissue in their sensitivity to change fraction size? Α: α/β ratio

68 Fractionation schedule

69 Conventional treatment Gy/day 5 day/week. Total dose is usually higher than cgy for gross solid tumor.

70 Dose > 2 Gy/per fraction. Palliative: Short term: > 2 Gy/day, usually 3 Gy/day. Total dose is lower than curative dose. Eg. 3 Gy x 10 Fx. Curative Hypofractionation For organs with parallel functional structure such as lung and liver. If the dose can be conformed to tumor, hypofractionation is considered. Eg. Proton treatment in hepatoma and lung cancer. Sterotactic Radiosurgery: single dose

71 Hyperfractionation Decrease of fraction size < 1.8 Gy/fraction, usually Gy. Increase fraction number. Usually treat more than 1 fraction/per day. Purpose: Spare normal tissue (late complication tissue) when using smaller fraction size. If treated with similar dose as conventional treatment, complications are expected to decrease. If treated with the increased total dose, tumor control probability is expected to increase but same possibility of late complications.

72 Accelerated fractionation Method Same fraction size, Gy, same fraction number. Shorten total treatment time. Eg. bid (twice per day), or > 5 fractions/per week Purpose: Reduce tumor repopulation during RT. Limitation: Severe acute reaction.

73 Mixed type CHART (Continuous hyperfractionated, accelerated radiotherapy) Methods 150 cgy/fx. 3 fx./day, W1-7, total dose = 54 Gy. Total treatment time: 12 days. Results: Increased acute toxicity. Late complications: not increased except spinal cord. similar or slightly better local control for different types of tumor. Implication: Reduce repopulation

74 Mixed type ARCON -Accelerated Hyperfractionated Radiation Therapy while Breathing Carbogen and with the addition of Nicotinamide -Accelerated to overcome proliferation. -Hyperfractionated to spare normal tissues. -Carbogen breathing to overcome chronic hypoxia. -Nicotinamide to overcome acute hypoxia.

75 Basic biological principles in clinics 4 R : Repair: Fractionated treatment: sublethal damage repair,slow repair (such as spinal cord) Differences between tumor and normal tissue. Reoxygenation: hypoxia, OER, re-oxygenation during RT. Repopulation: accelerated repopulation Reassortment: cell cycle re-distribution after irradiation.

76 4 Rs and TDF Repair Tumor Early responding tissues Late responding tissues Reassortment Repopulation Reoxygenation Is there any gain between early responding tissue (or tumor) and late responding tissues

77 Tumor control probability (TCP) and normal tissue complication probability (NTCP) in radiotherapy

78 Tumor control probability (1) Assumption 1 cm 3 = 10 9 tumor cells Survival fraction of 2 Gy = 0.5 = ½ No repopulation during treatment, each dose has same killing effect Calculation 2 Gy x 2 = ½ x ½ 2 Gy x 3 = ½ x ½ x ½... 2 Gy x 10 = (1/2) 10 = 1/1024 = (10) -3 2 Gy x 30 = (1/2) 30 = (10) -9 2 Gy x 31 = (1/2) 31 = (10) -9 x ½

79 Tumor control probability (2) Calculation 1 cm 3 = 10 9 tumor cells After 28 treatment (2 Gy x 28) = 4 cells 29 treatment (2 Gy x 29) =2 cells 30 treatment (2 Gy x30) = 1 cell 31 treatment (2 Gy x 31) = 0.5 cell 32 treatment (2 Gy x 32) = 0.25 cell

80 Poisson distribution a n e -a P n = n! (P n =the probability of finding n survival cells) (a = expected number) Eg: n =1, a=1 1 1 e -1 P 1 = = 37% 1! (P 1 =the probability of finding 1 survival cells) (1 = expected number)

81 TCP with doses Dose (Gy) Cell (1/2) 28 (1/2) 29 (1/2) 30 (1/2) 31 (1/2) 32 (1/2) 33 killing Survivin g cells TCP

82 TCP with doses TCP (%) (Gy) )

為減少腫瘤治療時間, 提高治療過程的舒適度, 降低因身體蠕動而造成劑量給予的不確定性, 提升治療的精確度, 增加腫瘤局部控制率, 避免正常組織接受到不必要的劑量, 降低

為減少腫瘤治療時間, 提高治療過程的舒適度, 降低因身體蠕動而造成劑量給予的不確定性, 提升治療的精確度, 增加腫瘤局部控制率, 避免正常組織接受到不必要的劑量, 降低中華民國生物醫學工程學會腫瘤醫學影像暨治療儀器新知研討會主辦單位 : 澄清綜合醫院中港分院 / 中華民國生物醫學工程學會會議日期 :101 年 12 月 22 日 ( 星期六 ) 會議地點 : 澄清醫院中港分院 17 樓國際會議廳 ( 台中市中港路