放射線治療的併發症謝忱希

放射治療的併發症

謝忱希醫師

亞東紀念醫院放射腫瘤科主治醫師國立陽明大學傳統醫藥研究所醫學博士

哈佛麻省總醫院 Francis H. Burr 質子治療中心研究

腫瘤的分類

上皮癌(Carcinoma) 肉瘤(Sarcoma)

胚胎來源

外胚層原始中胚層, 外胚層的

Schwann cells, 血管的內皮

內襯(endothelial lining)和間

皮(mesothelium)。

組織學

黏膜層(mucosa) 黏膜下層(submucosa)的結

締組織(connective tissue)

病理學

腺癌、鱗狀細胞癌、移行細

胞癌、小細胞癌、分化不良

癌等等。

種類很複雜

發生率佔大多數的癌症。發生率卻不到所有癌症的1%。

常見癌症治療方式

何謂放射治療(以下簡稱RT)

• 使用放射線治療疾病

• 廣泛用於惡性腫瘤(癌症)，良性腫瘤，預防冠狀動脈再阻塞，抗排斥等

Rontgen discovers x-rays in 1895

ＲT 給予方式

• 遠隔治療(Teletherapy) ：

– 使用離開身體之射源

• 近接治療(Brachytherapy)：

– 使用接近或在體內之射源

遠隔治療(Teletherapy)

• 俗稱外電

• 機器：

1.鈷六十治療機(Co-60)

2.直線加速器(Linear accelerator)：可放出光子(photon)或電子(electron)射束

3.導航螺旋刀

4.質子(proton)及中子(neutron)

體外放射治療技術之演進

1960’

二維定位

放射治療

1980’

三維適形

放射治療

1990’

強度調控

放射治療

2000’

影像導引

放射治療

2D radiotherapy

3D conformal

radiotherapy

(3DCRT)

Intensity Modulated

Radiotherapy

(IMRT)

Image guided

Radiotherapy

( IGRT)

•

高精確

•

高劑量

•

高效率

•

低損傷

導航螺旋刀

銳速刀第一代

第二代

第三代

第四代

傳統放射線治療

Linear accelerator

肺癌: 治療前肺癌: 治療後

IMRT + 化學治療

RapidArcTM

• 體積弧形放射治療。

• 利用直線加速器旋轉一次(360度)或多次(小於360度)

傳送一個的三度空間(3D)劑量分布。

• 縮短治療所需時間。

Volumetric Modulated Arc Therapy;

VMAT

• 整合IMRT及IGRT功能的技術設備

Tomotherapy

• Increased treatment precision and accuracy

– Image Guided delivery (3D)

Clinical trends in Radiation Therapy

Proton therapy

Swanson EL, et al. Int J Radiat Oncol Biol Phys 2012 Jan 21. [Epub ahead of print]

IMRT vs IMPT – Dose distribution

IMRT IMPT IMRT IMPT Taheri-Kadkhoda Z, et al. Radiat Oncol. 2008 Jan 24;3:4.

• 特性：

1.光子治療較深層之腫瘤

2.電子治療較淺層之腫瘤

3.鈷六十可治療深層之腫瘤，但是皮膚反應較大

4.質子可使正常組織劑量降至最低

近接治療(Brachytherapy)-射源

• 俗稱: 內電

• 射源

– 銥-192 (Ir-192)

– 金-198 (Au-198)

– 碘-125 (I-125)

– 銫-137 (Cs-137)

近接治療(Brachytherapy)

--方式

• Interstitial implant(組織間插種)：

如插針或植入同位素顆粒

• Intracavity/Intraluminal(腔內治療)：

– 如：Cx Ca 放裝置入 vagina or uterus

– 如：Bronchogenic Ca 放裝置入 Bronchus

– 如：NPC 放裝置入 Nasopharynx

Brachytherapy

放射治療之原理

1.利用放射線殺死腫瘤細胞，使其走向凋亡（apoptosis)

2.正常組織細胞則可在受損之後修復

為何 RT 要分多次給予

1.腫瘤細胞在細胞週期的 G2/M phase 最易被放射線殺死，故分次後可使非 G 2 / M

p h a s e 之細胞走入G2/M phase 而被殺死

2.正常組織細胞在兩次照射之間，將有機會修復

放射治療的劑量

•單位: 雷得 (rad, cGy), 葛雷 (Gy)

100雷得=1葛雷。

•通常一天一次給予180-200 雷得。

或一天兩次給予110-120 雷得。

•緊急或緩和治療時一天一次給予300-400雷得。

RT之角色

1.Radical intent(根治性):

如 NPC, Cx Ca等

2.Adjuvant / Neoadjuvant intent(輔助性):

術前或術後之輔助性治療

3.Palliative intent(緩和性):

for metastasis or symptom relieve

4.Emergent RT:

如 tumor bleeding, obstruction, spinal cord compression or SCV syndrome etc.

放射增敏劑與放射保護劑

• 使用放射增敏劑 (radiosensitizer):

如 5-FU, IUdR, Misonizazole 等，使腫瘤對放射治療更敏感

• 使用放射保護劑 (radioprotector):

如 Amifostine (WR2721) 等，以減少正常組織之傷害

Tomo plan

Pinnacle

plan

放射治療之流程

治療計劃方向

1.使腫瘤得到足夠劑量

2.儘量減少正常組織劑量

3.Critical organ tolerance:

Spinal cord: 45Gy

Brain: 50Gy

Optic nerve: 54Gy

Lens: 2Gy

Liver: 30Gy

Kidney: 23Gy

RT reactions

• 早期反應（前六個月）

– Mucositis: oral & intestine

– Dermatitis

– Hair loss

Mucositis

Ulceration

Mucositis

Dermatitis

Grade 4

Grade 1

Radiation pneumonitis

Shueng PW, et al, Radiat Oncol. 2009 Dec 31;4:71.

The dose distribution of radiotherapy

designed for tomotherapy.

Chest computed tomography (CT) post

intubation in the MICU shows interstitial pattern

with traction

Bronchiectasis consolidation and fibrosis in the

bilateral lung fields.

• 晚期反應（六個月之後）

– Xerostomia, loss of

taste

– osteoradionecrosis

– brain necrosis

– spinal cord myelitis

– trismus

– skin fibrosis

– hypopituitarysm

– hypothyroidism

放射治療的副作用及處理

• 與照射部位有關

• 頭頸癌照射:

第一至三次:想嘔吐--喝運動飲料

口乾舌燥--用蒸氣吸入器

脖子和喉嚨腫脹--會自消

第八至十次:喉頭異物感--吃高蛋白食物

口水黏稠--蘇打水漱口

第十二至十五次:喉嚨吞就痛及口腔黏膜炎--吃軟且

溫和之高蛋白,蘇打水漱口

第二十至二十五次:痰多喉嚨癢--多喝水吸蒸器,勿用

力咳嗽

第二十八至三十次:食之無味--吃維他命B12二月恢復

耳朵積水--看耳鼻喉科

放射治療的副作用及處理

• 腦部照射後掉髮會再慢慢長出

• 婦癌照射:

第一至三次:想嘔吐,吃不下,下腹脹--吃止吐及助消

化藥

第五至十次:分泌物多或帶血--要沖洗

第十一至十五次:頻尿,陰癢--多喝水不憋尿保持乾燥

第十六次至結束:腹瀉,腸蠕動快,體力差--吃止瀉藥

或適度點滴

• 乳癌照射: 注意破皮

• 飲食方面: 要均衡,忌:菸,酒,辛辣,刺激性食物

PT 可能可著力的的範圍

• Trismus

• Pulmonary function training

• …….

Trismus

• The prevalence of trismus in head and neck

cancer

– 5% to 58.5%.[1-6]

• Reported incidences of trismus in NPC after

radiotherapy

– 5% of 17%.[4,7-11] 1. Steelman R, et al. Mo Dent J 1986:66: 21–23.

2. Thomas F, et al. Int J Radiat Oncol Biol Phys 1988:15: 1097–1102.

3. Yeh SA, et al. Int J Radiat Oncol Biol Phys. 2005;62:672-679.

4. Qin DX, et al. Cancer.1988;61:1117-1124.

5. Chen M, et al. Chin J Cancer. 2001;20:651-653.

6. Dijkstra et al. Oral Oncol. 2004;40:879-889.

7. Huang SC. Int J Radiat Oncol Biol Phys 1980;6:401–407.

8. Haghbin M, et al. Am J Clin Oncol 1985;8:384–392.

9. Hoppe RT et al. Cancer 1976;37:2605–2612.

10. Mesic JB, et al. Int J Radiat Oncol Biol Phys 1981;7:447–453.

11. Tuan JK, et al. Radiother Oncol. 2012 Jan 24. [Epub ahead of print]

Definition of trismsus

• It has been defined as a mouth-opening capacity from <20 mm up to 40 mm.[1]

• A mouth opening of 35 mm or less should be regarded as indicative of trismus for head and neck oncology patients.[2]

• The SOMA [3]

– Grade 2: 1.0 cm to 2.0 cm

– Grade 3: 0.5 cm to 1 cm

– Grade 4: <0.5 cm

• Trismus also can be defined as a mouth-opening size <30 mm [4]

– Normal: size >30 mm

– Moderate trismus: 20-30 mm

– Severe trismus: <10 mm.

1. Dijkstra PU et al.Oral Oncol. 2004;40:879-889.

2. Dijkstra PU, et al. Int J Oral Maxillofac Surg 2006;35:337–342

3. LENT SOMA tables. Radiother Oncol. 1995;35:17-60.

4. Sakai S, et al. Cancer. 1988;62:2114-2117.3.

Definition of trismsus

• Chen YY, et al [1]

– Grade 1: 20-30 mm.

– Grade 2: 1.0 cm to 2.0 cm

– Grade 3: 0.5 cm to 1 cm

– Grade 4: <0.5 cm

• CTCAE v4.02

– Grade 1: Decreased ROM (range of motion) without impaired eating.

– Grade 2: Decreased ROM requiring small bites, soft foods or purees

– Grade 3: Decreased ROM with inability to adequately aliment or hydrate orally

1. Chen YY, et al. Cancer. 2011;117(13):2910-6.

Measurement of trismsu

• Maximal interincisal distance or opening

(MID/MIO)

– Measures with calipers

Wang CJ et al. Laryngoscope. 2005 Aug;115(8):1458-60.

Risk factors

• The mean maximum interincisal opening (MIO)

– MIO <35 mm> mean: 51 mm.[2]

• The trismus patients also had significantly

– Larger tumors (p=0.0437),[2]

– Advanced T status (P=0.0001) [1]

– Young age (P=0.0001),[1]

– Physical function before start of treatment (p=0.0344), [2]

– Received a higher total tumor radiation dose (p=0.0418).[2]

1. Ozyar E, et al. Radiother Oncol. 2005;77(1):73-6.

2. Johnson J, et al. Med Sci Monit. 2010 Jun;16(6):CR278-82.

Risk factors

• The severity of trismus is dependent on

– the configuration of the radiation field,

– the radiation source

– the radiation dose. [1-3]

1. Vissink A, et al. Crit Rev Oral Biol Med 2003;14:199–212.

2. Goldstein M, et al Oral Surg Oral Med Oral Pathol Endod 1999;88:365–73.

3. Wollin M, et al. Med Phys 1976;3:113–6.

Structure

Masseter

Temporalis

Med. Pterygoid

Lat. Pterygoid

Mandibular condyle

Muscle, tissue for trismsus

• Patients with NPC and oropharyngeal

carcinoma are prone to suffer trismus after

RT

– They are at great risk of receiving high

radiation doses to the TMJ structure.[1,2,3]

1. Chen YY, et al. Cancer. 2011;117(13):2910-6.

2. Goldstein M, et al. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1999;88:365–373

3. Steelman R, MO Dent J1986;66:21–3.

Muscle, tissue for trismsus

• Direct RT effect on masticator muscles (N=35)

– Medial pterygoid 11 (31%)

– Lateral pterygoid 16 (45%)

– Masticator 5 (14%)

– Temporalis 4 (11%)

– Total=19 (54%)

• Masticator muscle atrophy secondary to V3 nerve palsy

– 1 (3%)

• RT-related mandibular abnormality

– Temporomandibular joint deformity 5 (14%)

– Ramus osteoradionecrosis 5 (14%)

– Total=8 (23%)

Bhatia KS, et al. Eur Radiol. 2009;19(11):2586-93.

Jaw-stretching devices

Lund TW, et al . Quintessence Int 1993;24:275-279

Can exercises improve the

trismus?

A mobilization regimen to prevent mandibular

hypomobility in irradiated patients:

An analysis and comparison of two techniques

• Group 1:

– A control (no exercise)

• Group 2:

– Buchbinder techniques.

• Group 3:

– Santos techniques.

Grandi G, et al. Med Oral Patol Oral Cir Bucal. 2007 1;12(2):E105-9

Buchbinder technique

• Instructions - exercises buccal opening recommendations: The exercises will have to be made 6 times to the day

• - To open mouth maximum that to obtain – count 3 seconds with open mouth and to close - to make this 10

times;

• - Chin for the right side – count 3 seconds in this position and to come back ploughs the

normal position - to make this 10 times;

• - Chin for the left side – count 3 seconds in this position and to come back ploughs the

normal position - to make this 10 times;

• - Onward chin – count 3 seconds in this position and to come back toward the

normal position - to make this 10 times.

Santos techniques

• The exercises will always have to be carried through in the same schedule, 3 times per day, after breackfast, lunch and dinner.

• - To open mouth maximum – count 3 seconds with open mouth and to close - to make this 5 times

• - Chin for the right side, – count 3 seconds in this position and to come back toward the normal

position - to make this 5 times

• - Chin for the left side, to count 3 seconds in this position and to come back toward the normal position - to make this 5 times

• - Onward chin, to count 3 seconds in this position and to come back toward the normal position - to make this 5 times.

• Immediately after to make the exercises, chews 2 tablets of gum to chew (trydentr) per 15 minutes.

• These exercises have to be maked every day while you are having radiotherapy

No statistically significant differences

Mobilization regimens for the prevention of jaw

hypomobility in the radiated patient: a

comparison of three techniques

• Three groups of patients

– Unassisted exercise

– Mandibular mobilization with stacked tongue depressors combined with unassisted exercise,

– Therabite System combined with unassisted exercise.

• The initial average maximum incisal opening (MIO)

– 21.6 mm.

• At week 6 and thereafter, the net increase in MIO

– Group 1: 6.0 mm (+/- 1.8)

– Group 2: 4.4 mm (+/- 2.1)

– Group 3: 13.6 mm (+/- 1.6)

• There was no statistical difference between groups 1 and 2.

Buchbinder D, et al. J Oral Maxillofac Surg. 1993;51:863–7

A Randomized Preventive Rehabilitation Trial in Advanced Head

and Neck Cancer Patients Treated with Chemoradiotherapy:

Feasibility, Compliance, and Short-term Effects

• The S rehabilitation

– Range-of-motion

exercises

– Three strengthening

exercises.

• the effortful swallow,

the Masako maneuver,

and the super-

supraglottic swallow.

• The stretch exercise of the E rehabilitation

– A passive and slow opening of the mouth

• using the Thera-Bite device.

– The strengthening exercise consisted of swallowing with the tongue elevated to the palate

• Maintaining mouth opening at 50% of its maximum, (training the suprahyoid muscles)

van der Molen L, et al. Dysphagia. 2011 Jun;26(2):155-70

Instructions Standard Rehabilitation

Instructions TheraBite® Rehabilitation

A Randomized Preventive Rehabilitation Trial in Advanced

Head and Neck Cancer Patients

Treated with Chemoradiotherapy:

Feasibility, Compliance, and Short-term Effects

• Comparing the pre- and post-treatment maximum mouth opening (MIO) – a significant decrease over time was found (from 50 to 47 mm,

respectively; p < 0.01).

– Not in occurrence of trismus (MIO<35 mm; from 5 to 7 patients; p = 0.70).

van der Molen L, et al. Dysphagia. 2011 Jun;26(2):155-70

Can exercises improve the trismus?

• Patients who applied the exercises described

by compared to those who did not exercise

– A trend toward better results. [1,2,3]

1. Grandi G, et al. Med Oral Patol Oral Cir Bucal. 2007 1;12(2):E105-9..

2. Buchbinder D, et al. J Oral Maxillofac Surg. 1993;51:863–7.

3. van der Molen L, et al. Dysphagia. 2011 Jun;26(2):155-70

Can exercises improve the

pulmonary capacity and

improve survival?

Exercise Testing, 6-MmWalk,andStair

Climb in the Evaluation of Patients at High

Risk for Pulmonary Resection

• Patients with an FEV1 < 1.60 L

– ↑ risk of surgical morbidity and mortality and require additional preoperative testing.

• FEV1% < 45 % and FEV1%PPO < 40 % – identify a subset at even higher risk.

• A 6-min walk (6MWT) distance of 1,000 feet and a stair climb of > 44 steps – As threshold values to determine surgical

morbidity and mortality requires further prospective evaluation.

Holden DA, et al. Chest 1992;102;1774-1779

6 MW > 400 m:

a useful prognostic factor for survival in patients

with advanced non-small cell lung cancer. • NSCLC stage IIIA, IIIB, or IV, ECOG-PS 0 to 2 and with a life

expectancy of at least 4 months were included.

• Six-Minute Walk – Instructs to cover as much distance as possible

• participants walked up and down a 30-m hallway for the allotted 6 minutes.

• Patients were instructed to walk at their own pace and were advised to slow down or stop as needed.

• Resume walking as soon as they felt they were able to do so.

– At the end of 6 minutes • The distance covered was measured by the instructor.

– Dyspnea was measured by the Borg scale, oxygen saturation and pulse rate were assessed at the start and end of 6MW.

Kasymjanova G, et al. J Thorac Oncol. 2009;4: 602–607

6MW > 400 m:

a useful prognostic factor for survival in patients

with advanced non-small cell lung cancer. Survival curve during the initial 6MW test

Patients who walked > 400 m (n = 35) and who walked < 400 m (n = 29).


Walked > 400 m

A 6-MW 400 m identified lung cancer

patients with less toxicity after radiation

therapy

• A prospective trial to study radiation

therapy–induced lung injury

– A pre-RT 6MWT was performed in 41 patients.

– The predictive capacities of pre-RT 6MWT

• Forced expiratory volume in 1 s (FEV1)

• Single-breath diffusing capacity for carbon

monoxide (DLCO) for the development of RTLI

were assessed with receiver operating curve (ROC)

techniques.

Miller KL, et al. Int J Rad Oncol Biol Phys 2005;62:1009 –1013

A 6-MW 400 m identified lung cancer patients

with less toxicity after radiation therapy


Can exercises improve the pulmonary

capacity and improve survival?

• 6 MWT could be a useful prognostic factor

for cancer patients under different

modalities treatment.

Holden DA, et al. Chest 1992;102;1774-1779



• Physical therapists have roles to improve

the side effects caused by radiotherapy.

Thank you for your attention!

放射線治療的併發症 謝忱希

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放射線治療的併發症謝忱希