11

R E V I E W A R T I C L E

Management of peripheral neuropathy for cancer patients

서 론

암환자에서신경병, 혹은말초신경병증은흔하고종종환자를매

우힘들고쇠약하게만든다. 이들신경병증의원인은암의침습,

암과관련되거나혹은암치료의합병증에서기인한다. 암과관련

된신경병을보다효과적으로치료하기위해서는무엇보다조기

에진단하는것과환자개인이갖고있는선행혹은동반질환을

이해하는것이무엇보다중요하다. 다학제간협진으로근거중심

의학에의거하여다양한암치료전문가들은보다근거있고활발

한연구가필요한분야를심도있게논의하여암신경병증의예

방, 진단 및 치료를 위한 새로운 전략이 필요하다1,2. 여기서는

암관련신경병의일반적인개요를열거하고신경병증의사정평

가의기준및진단, 예방법그리고치료의현황과활발히연구되

고있는분야에대하여살펴보고자한다.

본 론

암관련신경병증

1) 정의(Definition) 와빈도(Incidence)

신경병증또는말초신경병증은‘말초신경의섬유의손상, 기능이

상으로유발되는상태’로정의할수있다’. 말초신경병증의증상

은두뇌및척수를연결하는신체의나머지에연결되어있는감각

신경, 자율신경, 운동신경의관련증상으로나눌수있다.1

말초신경계의중요한해부학적경계는신경근, 신경총및주변

신경을포함한다. 즉, 신경총의원위부위를신경병및말초신경

병이라하지만일반적으로말초신경계의위치는원인질환의병

리에따라서영향받는다.

신경병증은지금까지 100여가지이상의유형이알려져있으며,

각기특정한증상과경과, 예후를보인다. 신경병증의발생연령

은주로55세이상에서나타나며빈도는일반인구의약3~ 4%로

나타나며원인선행질환의1/3 이당뇨병, 나머지2/3 가특발성

으로나타난다.1,2

암환자의신경병증은또한항암화학요법약제등약물을포함한

다양한요인, 유전, 자가면역질환, 감염, 영양결핍및대사불균

형에서도유래할수있다.1 항암치료중이거나다른치료의합병

증으로인하여대게영양과대사의불균형이초래되는경우가많

아 암 환자는 신경병 발병의 위험에 그만큼 많이 노출되어있는

것이다.

최근암환자에서신경병증은흔하며암자체나치료와관련된합

병증으로인하여면역방어기능의저하, 치료의중단등환자는

심각한상태와경과로도이어질수있다. 이러한심각성으로인

하여이미 2009년NCCN의여러전문가들도Task Force 팀을

구성하여 암 환자의 신경병의 평가 그리고 관리에 대하여 심도

있게토의한바있다.2,3

2) 암관련신경병증의원인(Cause)

암신경병증은다양한원인으로부터발생할수있으며, 약물 (항

암제), 유전, 자가면역질환, 감염, 영양결핍, 대사이상등이있다.

1-3 (Table 1)

3) 증상과증후의특징(Signs and Symptoms)

신경병증의 정도는 단순한 불편에서부터 일상생활이 불가능할

정도로환자를현저히쇠약하게하는등매우위중할정도로매

Management of peripheral neuropathy for cancer patients

암환자에서말초신경병증의치료

연세대학교원주의과대학외과학교실 김익용

Yonsei University Wonju College of Medicine Wonju, Korea

Ik Yong Kim, M.D.

책임저자 : 김익용

220-701, 강원도원주시일산동 162번지연세대학교원주의과대학외과학교실

Tel: 033-741-0573 Fax: 033-744-6604 E-mail: iykim@yonsei.ac.kr

접수일 : 2011년 5월 23일 ; 게재승인일 : 2011년 6월 20일

M. P. Coleman, D. Alexe, T. Albreht & M. Mckee (Eds.).

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breast cancer. Psycho-Oncology, 14, 1075-1082.

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expressive coping predicts psychological and physical adjustment

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Branstetter, A., Rodriguez -Hanley, A., Kirk, S., & Austenfeld, J.

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10 Eun Young Park

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Korean Journal of Clinical Oncology Summer 2011;Vol.7,NO.1:

어결국생존기간에도잠재적으로영향을미칠수있다. 또한, 항

암화학요법과 같은 치료로 인한 신경병적 증상은 치료의 지연,

약제 용량의 감소가 요구되거나, 또는 치료의 중단으로 인하여

결국암치료성적과생존에도영향을미칠수있다.

항암제의 의한 말초신경병증 (Chemotherapy-Induced

Peripheral Neuropathy; CIPN)

화학요법에 의하여 유도된 말초 신경병은 현재, 다양한 약제의

출현으로더이상드문합병증이아니다. 이들항암제에의한신

경병은 주요한 용량-의존 독성이다6. CIPN의 연구는 광범하게

보고되고있으며현재가장많은연구가진행중이다. 말초신경

병증증을 일으키는 것으로 알려진 항암제는 platinum

compounds, taxanes, vinka alkaloids, bortezomib,

thalidomide 등이있으며약물의종류, 용량, 강도에따라신경

병증의정도가다르다6,7. (Table 3)

대장암을 비롯한 위장관암에 주로 사용되는 백금화합물인

oxaliplatin의신경병은발생시기에따라급성과만성으로나눈

다4,6. 급성증상은환자의85-95%에서경험하는데입주위와사

Management of peripheral neuropathy for cancer patients

우다양하다. 증상의시작은갑작스럽거나혹은점차적으로느리

게나타날수있으며감각신경병증의대표적인증상은손이나발

의통증과무감각증등이다. 처음에, 환자는종종쑤시며, 자발성

통증 (Spontaneous shooting), 또는 마비 같이 이상한 감각을

간헐적(Intermittently)을 느낀다. 점차보행시어려움, 물건을

떨어뜨리게된다. 특징적인감각의저하나소실은흔히얇은스

타킹이나 장갑을 착용하고 있는 것처럼 감각에 비유되며 간혹,

이러한 증상을 지속적(Continuous burning pain)으로 느끼는

어려움등을호소한다. 운동신경이손상되면근력의약화와근육

위축이올수있고자율신경과관련해서는환자는설사또는변

비, 요실금, 기립성저혈압, 불규칙한박동, 또는호흡곤란등의

증상이나타날수있다2-4.

체성감각 장애와 감각이상(paresthesia), 통각과민

(hyperalgesia), 이상감각(dysesthesia), 혹은이질통(allodynia)

의소견을보인다. 신경병성통증은신경조직손상과관련된불쾌

한감각과감정의경험으로정의하며촉발인자, 자극여부에따라

다양한증상의차이가있다.(Table 2)

감각이상은찌릿하고전기자극적이거나따끔거리는감각이다.

예를들면, 수근골증후군(Carpal Tunner Syndrome) 환자의

정중신경의 바닥면을 두드릴 때, 유발되는 감각 이상증상 등이

그 예이다. 통각과민은 통증이 증가된 상태로 신경의 재생과정

동안발생한다. 이상감각은자발적이거나자극되었을때불편한

감각이다5. 이질통은 정상적으로 통증을 유발하지 않는 자극에

반응하는 통증이다. 이질통의 예는 복합부위통증증후군환자가

손상된팔을스치는바람의미세한움직임에도방사통등의통증

을경험하는것과흡사하다.

4)암환자의신경병증(Neuropathy in Cancer)

암환자에서신경병의경과는더심각하여이로인하여삶의질을

떨어뜨리고일상생활을방해하거나, 무력감, 장애를초래하게되

12 Ik Yong Kim

Cause

Neurotoxicity related cancer treatment

Tumor pathology

Nutritional deficiencies

Metabolic disturbances

Opportunistic infections

Paraneoplastic neurologic disorders (PND), or

nervous dysfunction caused by the remote effects

Table 1. Cancer-related causes Neuropathy

such as surgery, radiotherapy, and chemotherapy

direct compression or infiltration of nerves by primary or metastatic lesions

Spontaneous pain Burning, shooting, lancinating

Hyperesthesia (increased feeling) increased sensitivity to stimulation, excluding the special senses

Paresthesia (Beyond feeling) abnormal nonpainful sensation that may be spontaneous or evoked (tingling)

Dysesthesia (impaired feeling) abnormal pain that may be spontaneous or evoked (unpleasant tingling)

Hyperalgesia (increased pain) an exaggerated painful response to abnormally noxious stimulus

Hyperpathia (increased suffering') an exaggerated painful response evoked by noxious or non-noxious stimulus

Allodynia (other pain) a painful response to a normally non-noxious stimulus(for example, light touch is perceived as burning

pain) involves a change in quality of sensation, whether touch or heat or cold

Hypoesthesia (decreased feeling') decreased sensitivity to stimulation, excluding the special senses

Hypoalgesia (decreased pain') diminished pain in response to a normally painful stimulus

Analgesia ('no pain') complete loss of pain sensation, namely absence of pain in response to stimulation which would

normally be painful

1.Sensory nerves affect sensation Painful paresthesia, dysesthesia, cold-sensitivity, tingling, numbness, alteration in vibration and

proprioception, or a change in reflexes

2.Motor nerves affect muscles and motion Muscle weakness

3.Autonomic nerves affect internal organs Orthostatic hypotension, constipation, urinary retention, irregular heart rate, and sexual dysfunction.

Table 2. The abnormal sensation of neuropathic pain

Drug Incidence Onset Dose Clinical Manifestation Recovery

Platinum compounds 28%-100% (overall) 300 mg/m2 Symmetrical painful paresthesia or Partial, symptoms may

Cisplatin + paclitaxel: 7%-8% numbness in a stocking-glove distribution, progress for months after

(severe*) sensory ataxia with gait dysfunction discontinuation

Carboplatin 6%-42% (overall) 800-1600 mg/m2 Similar to cisplatin but milder Similar to cisplatin

+ paclitaxel: 4%-9%

(severe)

Oxaliplatin (acute) 85%-95% (overall) any Cold-induced painful dysesthesia Resolution within a week

Oxaliplatin (persistent/ FOLFOX: 10%-18% 750-850 mg/m2 Similar to cisplatin Resolution in 3 months, may

chronic) (severe) persist long-term

Vinca alkaloids 30%-47% (overall) 4-10 mg Symmetrical tingling paresthesia, loss of Resolution usually within

Vincristine, vinblastine, ankle stretch reflexes, constipation, 3 months, may persist for

vinorelbine, vindesine occasionally weakness, and gait dysfunction vincristine

Taxanes 57%-83% (overall), 100-300 mg/m2 Symmetrical painful paresthesia or Resolution usually within 3 months,

Paclitaxel 2%-33% (severe) numbness in stocking-glove distribution, may persistmay persist

+ Cisplatin: 7%-8% decreased vibration or proprioception,

(severe) occasionally weakness, sensory ataxia,

+ Carboplatin: 4%-16% and gait dysfunction

(severe)

Abraxane (albumin-bound 73% (overall) unclear Similar to paclitaxel Resolution usually within 3weeks

paclitaxel) 10%-15% (severe)

Docetaxel 11%-64% (overall) 75-100 mg/m2 Similar to paclitaxel Resolution usually within 3 months,

3%-14% (severe) may persist

Others

Bortezomib 31%-55% (overall) 1.3 mg/m2 Painful paresthesia, burning sensation, Resolution usually within 3 months,

9%-22% (severe) occasionally weakness, sensory ataxia, may persist

and gait dysfunction. Rare autonomic

dysfunction including orthostatic hypotension

Ixabepilone 63% (overall), 14% 40-120 mg/m2 Painful paresthesia, burning sensation Resolution in 4-6 weeks

(severe)

+ capecitabine:

67% (overall), 21%

(severe)

Thalidomide 25%-83% (overall), 20 g Symmetrical tingling or numbness, pain. May persist for over 1 year

15%-28% (severe) Occasionally weakness, sensory ataxia,

and gait dysfunction

Lenalidomide 10%-23% (overall), unclear Similar to thalidomide Unclear

(thalidomide analog) 1%-3% (severe)

Table 3. Common Chemotherapeutic drugs Known to Induce Neuropathy

*Dose-limiting or grade 3 or 4 neuropathy according to the grading scale used by the study authors.

Adapted from Stubblefield MD, Burstein HJ, Burton AW, Custodio, CM, Deng GE, Ho M et a.l NCCN Task Force Report: Management of Neuropathy in Cancer. J NCCN 2009; 7: S5;1-35

13

Korean Journal of Clinical Oncology Summer 2011;Vol.7,NO.1:

어결국생존기간에도잠재적으로영향을미칠수있다. 또한, 항

암화학요법과 같은 치료로 인한 신경병적 증상은 치료의 지연,

약제 용량의 감소가 요구되거나, 또는 치료의 중단으로 인하여

결국암치료성적과생존에도영향을미칠수있다.

항암제의 의한 말초신경병증 (Chemotherapy-Induced

Peripheral Neuropathy; CIPN)

화학요법에 의하여 유도된 말초 신경병은 현재, 다양한 약제의

출현으로더이상드문합병증이아니다. 이들항암제에의한신

경병은 주요한 용량-의존 독성이다6. CIPN의 연구는 광범하게

보고되고있으며현재가장많은연구가진행중이다. 말초신경

병증증을 일으키는 것으로 알려진 항암제는 platinum

compounds, taxanes, vinka alkaloids, bortezomib,

thalidomide 등이있으며약물의종류, 용량, 강도에따라신경

병증의정도가다르다6,7. (Table 3)

대장암을 비롯한 위장관암에 주로 사용되는 백금화합물인

oxaliplatin의신경병은발생시기에따라급성과만성으로나눈

다4,6. 급성증상은환자의85-95%에서경험하는데입주위와사

Management of peripheral neuropathy for cancer patients

우다양하다. 증상의시작은갑작스럽거나혹은점차적으로느리

게나타날수있으며감각신경병증의대표적인증상은손이나발

의통증과무감각증등이다. 처음에, 환자는종종쑤시며, 자발성

통증 (Spontaneous shooting), 또는 마비 같이 이상한 감각을

간헐적(Intermittently)을 느낀다. 점차보행시어려움, 물건을

떨어뜨리게된다. 특징적인감각의저하나소실은흔히얇은스

타킹이나 장갑을 착용하고 있는 것처럼 감각에 비유되며 간혹,

이러한 증상을 지속적(Continuous burning pain)으로 느끼는

어려움등을호소한다. 운동신경이손상되면근력의약화와근육

위축이올수있고자율신경과관련해서는환자는설사또는변

비, 요실금, 기립성저혈압, 불규칙한박동, 또는호흡곤란등의

증상이나타날수있다2-4.

체성감각 장애와 감각이상(paresthesia), 통각과민

(hyperalgesia), 이상감각(dysesthesia), 혹은이질통(allodynia)

의소견을보인다. 신경병성통증은신경조직손상과관련된불쾌

한감각과감정의경험으로정의하며촉발인자, 자극여부에따라

다양한증상의차이가있다.(Table 2)

감각이상은찌릿하고전기자극적이거나따끔거리는감각이다.

예를들면, 수근골증후군(Carpal Tunner Syndrome) 환자의

정중신경의 바닥면을 두드릴 때, 유발되는 감각 이상증상 등이

그 예이다. 통각과민은 통증이 증가된 상태로 신경의 재생과정

동안발생한다. 이상감각은자발적이거나자극되었을때불편한

감각이다5. 이질통은 정상적으로 통증을 유발하지 않는 자극에

반응하는 통증이다. 이질통의 예는 복합부위통증증후군환자가

손상된팔을스치는바람의미세한움직임에도방사통등의통증

을경험하는것과흡사하다.

4)암환자의신경병증(Neuropathy in Cancer)

암환자에서신경병의경과는더심각하여이로인하여삶의질을

떨어뜨리고일상생활을방해하거나, 무력감, 장애를초래하게되

12 Ik Yong Kim

Cause

Neurotoxicity related cancer treatment

Tumor pathology

Nutritional deficiencies

Metabolic disturbances

Opportunistic infections

Paraneoplastic neurologic disorders (PND), or

nervous dysfunction caused by the remote effects

Table 1. Cancer-related causes Neuropathy

such as surgery, radiotherapy, and chemotherapy

direct compression or infiltration of nerves by primary or metastatic lesions

Spontaneous pain Burning, shooting, lancinating

Hyperesthesia (increased feeling) increased sensitivity to stimulation, excluding the special senses

Paresthesia (Beyond feeling) abnormal nonpainful sensation that may be spontaneous or evoked (tingling)

Dysesthesia (impaired feeling) abnormal pain that may be spontaneous or evoked (unpleasant tingling)

Hyperalgesia (increased pain) an exaggerated painful response to abnormally noxious stimulus

Hyperpathia (increased suffering') an exaggerated painful response evoked by noxious or non-noxious stimulus

Allodynia (other pain) a painful response to a normally non-noxious stimulus(for example, light touch is perceived as burning

pain) involves a change in quality of sensation, whether touch or heat or cold

Hypoesthesia (decreased feeling') decreased sensitivity to stimulation, excluding the special senses

Hypoalgesia (decreased pain') diminished pain in response to a normally painful stimulus

Analgesia ('no pain') complete loss of pain sensation, namely absence of pain in response to stimulation which would

normally be painful

1.Sensory nerves affect sensation Painful paresthesia, dysesthesia, cold-sensitivity, tingling, numbness, alteration in vibration and

proprioception, or a change in reflexes

2.Motor nerves affect muscles and motion Muscle weakness

3.Autonomic nerves affect internal organs Orthostatic hypotension, constipation, urinary retention, irregular heart rate, and sexual dysfunction.

Table 2. The abnormal sensation of neuropathic pain

Drug Incidence Onset Dose Clinical Manifestation Recovery

Platinum compounds 28%-100% (overall) 300 mg/m2 Symmetrical painful paresthesia or Partial, symptoms may

Cisplatin + paclitaxel: 7%-8% numbness in a stocking-glove distribution, progress for months after

(severe*) sensory ataxia with gait dysfunction discontinuation

Carboplatin 6%-42% (overall) 800-1600 mg/m2 Similar to cisplatin but milder Similar to cisplatin

+ paclitaxel: 4%-9%

(severe)

Oxaliplatin (acute) 85%-95% (overall) any Cold-induced painful dysesthesia Resolution within a week

Oxaliplatin (persistent/ FOLFOX: 10%-18% 750-850 mg/m2 Similar to cisplatin Resolution in 3 months, may

chronic) (severe) persist long-term

Vinca alkaloids 30%-47% (overall) 4-10 mg Symmetrical tingling paresthesia, loss of Resolution usually within

Vincristine, vinblastine, ankle stretch reflexes, constipation, 3 months, may persist for

vinorelbine, vindesine occasionally weakness, and gait dysfunction vincristine

Taxanes 57%-83% (overall), 100-300 mg/m2 Symmetrical painful paresthesia or Resolution usually within 3 months,

Paclitaxel 2%-33% (severe) numbness in stocking-glove distribution, may persistmay persist

+ Cisplatin: 7%-8% decreased vibration or proprioception,

(severe) occasionally weakness, sensory ataxia,

+ Carboplatin: 4%-16% and gait dysfunction

(severe)

Abraxane (albumin-bound 73% (overall) unclear Similar to paclitaxel Resolution usually within 3weeks

paclitaxel) 10%-15% (severe)

Docetaxel 11%-64% (overall) 75-100 mg/m2 Similar to paclitaxel Resolution usually within 3 months,

3%-14% (severe) may persist

Others

Bortezomib 31%-55% (overall) 1.3 mg/m2 Painful paresthesia, burning sensation, Resolution usually within 3 months,

9%-22% (severe) occasionally weakness, sensory ataxia, may persist

and gait dysfunction. Rare autonomic

dysfunction including orthostatic hypotension

Ixabepilone 63% (overall), 14% 40-120 mg/m2 Painful paresthesia, burning sensation Resolution in 4-6 weeks

(severe)

+ capecitabine:

67% (overall), 21%

(severe)

Thalidomide 25%-83% (overall), 20 g Symmetrical tingling or numbness, pain. May persist for over 1 year

15%-28% (severe) Occasionally weakness, sensory ataxia,

and gait dysfunction

Lenalidomide 10%-23% (overall), unclear Similar to thalidomide Unclear

(thalidomide analog) 1%-3% (severe)

Table 3. Common Chemotherapeutic drugs Known to Induce Neuropathy

*Dose-limiting or grade 3 or 4 neuropathy according to the grading scale used by the study authors.

Adapted from Stubblefield MD, Burstein HJ, Burton AW, Custodio, CM, Deng GE, Ho M et a.l NCCN Task Force Report: Management of Neuropathy in Cancer. J NCCN 2009; 7: S5;1-35

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Korean Journal of Clinical Oncology Summer 2011;Vol.7,NO.1:

경또한항암제에덜민감하다.

Platinum 계약물은DRG 에직접축적되어DRG 신경에DNA

변형과 형태변화, 새포자멸등으로 손상을 입힌다. Cisplatin 또

한axonal microtubule 성장의손상을준다. oxaliplatin 독성의

심각한형태는약에서유리된 oxalate 의해 칼슘킬레이트화와

연관이 있고 이는 이온교환(ion channels)와 시냅스전달

(synaptic transmission)에 영향을 미친다. cisplatin, taxanes

과vinca alkaloids 또한미세관(Microtubule)의손상을입혀축

삭운반(axonal transport)를방해한다2,3,7.

암환자신경병증의평가(Evaluation)

말초신경병증은골수기능억제, 식욕부진, 오심, 구토, 점막염등

항암치료로인한다른부작용에비하여치료하는의료진의관심

과중요도로부터상대적으로낮은비중을차지하는경향이있으

며, 주기적인사정이이루어지지않아정확한사정과관찰이안

되는경우도있다. 실제일부연구에서는의료진이환자자신보다

말초신경병증을더낮게평가하는경향이있다고도하였다.

실제임상에서도말초신경병증으로불편감을호소하는암환자를

자주경험하게되고, 이로인해항암치료를중단하게되는경우

Management of peripheral neuropathy for cancer patients

지에서감각이상이나타난다. 증상은일시적이며약제투여중이

나투여직후에발생하고저온에노출되었을때잘나타난다. 그

러나곧저절로증상은소실된다. 약제의투여횟수가증가할수록

더자주나타나는경향을보인다. 만성증상은dose-limiting 부

작용으로약제의투여횟수가누적되면서나타난다. 약 16%에서

3-4도 신경독성을 경험한다4,9,10. 증상은 주로 사지에 이상감각

(dysesthesias) 또는 감각이상(paresthesias)가 나타나고, 항암

요법주기사이에지속되며누적양이증가할수록증상이심해진

다6. 점진적으로 감각 장애로 진행되며 감각-운동기능이상

(sensory-motor nerve dysfunction) 에 의해 옷의 단추 잠그

기, 글쓰기, 물건잡기등이어려워진다. 그외tendon reflex의

소실, spasm 등이나타날수있다. 만성독성은급성에비해천천

히나타나지만회복도매우느리다. 만성독성은특징적으로약

제에 대한 종양반응이 나타난 이후에 주로 나타난다10,11. 약제의

투여량이중앙값874 mg/m2 (10 cycle)일때3도이상의신경독

성이나타나며투여종료후약13주후부터서서히회복되기시

작한다8-10.

1) 항암제의의한말초신경병증의임상양상

CIPN의임상증상중운동, 감각신경과관련한증상으로손가락,

발가락의저림(tingling), 둔한 느낌 (numbness), 타는 듯한느

낌(burning), 찌르는느낌(stabbing), 쑤시는느낌(shooting), 따

끔거림 (pricking) 등이며, 감각의 저하나 소실은, 일차적으로

polyneuropathic 하며대개양측성이고원위부위, 신경축의길

이 의존적으로 초기에는 손가락, 발가락 부터 증상이 나타난다

환자는흔히손과발에흔히얇은스타킹이나장갑을착용하고있

는것처럼이상감각(stocking-glove “dying back”)에비유된다

4,5,7. (Fig. 1)

이러한 길이 의존적인 원위부 양상의 (length-dependent,

distal Pattern) 증상은신경병이악화되는경우에상방까지진

행된다. 결국이러한긴섬유는CIPN 약제에노출될수있는가

장넓은표면을갖고있어서보다많은독성을나타낸다. CIPN

다발성 신경병증이 발전하는 때 수근 골 증후군(carpal tunnel

syndrome) 발견되는중앙신경(median nerve)손상과같은단일

신경병은CIPN을다발성신경병으로더악화시킬수있다.

증상은통증을느낄정도로악화될수있고심부건반사(DTR) 상

실, 진동, 온도, 접촉, 위치감각의상실로진행될수있다. 이런

증상은급성으로나타나거나경미하거나일시적이며항암요법

을종료한후회복되기도하지만일부의경우더악화되는경우

도있으며 (‘coasting effect’) 비가역적인상태로남을수있다.

대개는사용한항암제의누적용량과관련이있다.

2) 신경병의기전Mechanisms of Neuropathy

- 항암제에의한신경독성의기전 - (Neurotoxicity Mechanisms of

Chemotherapeutic and Biologic Agents

말초신경내에서 운동신경축삭(motor axons)은 크고 수초화

(myelinated) 되어있는 반면 감각신경 과 자율신경의 축삭

(axon)은 대부분 작거나 비수초화(unmyelinated) 혹은 thinly

myelinated 되어있다.

앞서언급한데로신경원위부양상의(length-dependent, distal

Pattern) 증상은신경병이악화되는경우에상방까지진행된다.

즉, 가장긴섬유는항암약제에노출될수있는가장넓은표면을

갖고있어서보다많은독성을나타낸다3,7.

Taxanes과 vinca alkaloids계의 약물은 축삭손상을 유발하여

소위 축삭병변(axonopathy)를 초래하고 Platinum계는 배근신

경절(Dorsal root ganglion; DRG)에영향을준다. 작은신경섬

유는비교적초기에빈번하게영향을받는다7,12. 이들은재생능력

이작고잘손상되어항암제에의한신경병증이특히감각신경의

이상이 많은 이유로 설명된다. 작은 감각 혹은 말초감각신경의

세포체가배근신경절에위치하며이는혈액-뇌관문(blood brain

barrier)를보호하고바깥에존재하여손상받기쉽다3.

DRG는또한전신혈류에투과성이높은모세혈관이풍부하여혈

액내에독성물질에잘노출된다. 운동세포는항암제에의한신

경병증빈도가적기도하고상대적으로약물신경손상이덜심각

하며재생능력이좋아환자의근력과기능회복이잘된다. 자율신

14 Ik Yong Kim

Fig. 1. Symptoms of chemotherapy-induced peripheral neuropathy.5

History

•Personal history of neuropathy and CIPN from previous cancer treatment

• Personal and family history of hereditary neuropathy (patients with Charcot-Marie Tooth disease should avoid vincristine-based chemotherapy)

•Related comorbid conditions (e.g., diabetes, HIV, Guillain-Barre syndrome, CIDP, radiculopathy)

•Alcohol use

•Temporal profile: regimen dosage, duration, schedule,°∞coasting°± effects

•Symptoms

•Type: sensory, motor, or autonomic

•Distribution: distal symmetric or asymmetric

•Severity

•Pain assessment: BPI, LANSS, NPS

•Time course of CIPN, including onset and resolution of symptoms

•Treatment delays or discontinuation related to CIPN

Physical Examination

•Sensory assessment: light touch, vibration, proprioception, pin-prick, temperature

•Deep tendon reflex: presence, absence, diminishment

•Motor weakness

•Autonomic symptoms (e.g., constipation, orthostatic hypotension, urinary dysfunction, sexual dysfunction)

•Related musculoskeletal abnormalities (e.g., hammertoes, high or flattened arches)

Sample Questions for Patient

•Do you feel numbness or tingling in your hands or feet?

•Do you feel pain in your hands and feet? (Rate it on a scale of 0 to 10.)

•Do you feel like having gloves and stockings on?

•Do these sensations bother you? Are they getting worse?

•Do you feel weakness in your arms and legs?

•Do you drop things often?

•Have you fallen recently?

•Do you have difficulty walking or climbing stairs?

•Do these sensations interfere with your work or daily activities?

Examples of Functional Assessment Skill Tests

•Getting up and straight-line walking (observe gait and balance)

•Name writing

•Buttoning

•Timed pellet retrieval (for clinical trials)

•Pegboard test (for clinical trials)

Table 4. Key Points to Report During Clinical Assessment of CIPN

Abbreviations: BPI, Brief Pain Inventory; CIDP, chronic idiopathic demyelinating polyneuropathy; CIPN,

chemotherapy-induced peripheral neuropathy; LANSS, Leeds Assessment of Neuropathic Symptoms and Signs Pain Scale;NPS, Neuropathic Pain Scale.

15

Korean Journal of Clinical Oncology Summer 2011;Vol.7,NO.1:

경또한항암제에덜민감하다.

Platinum 계약물은DRG 에직접축적되어DRG 신경에DNA

변형과 형태변화, 새포자멸등으로 손상을 입힌다. Cisplatin 또

한axonal microtubule 성장의손상을준다. oxaliplatin 독성의

심각한형태는약에서유리된 oxalate 의해 칼슘킬레이트화와

연관이 있고 이는 이온교환(ion channels)와 시냅스전달

(synaptic transmission)에 영향을 미친다. cisplatin, taxanes

과vinca alkaloids 또한미세관(Microtubule)의손상을입혀축

삭운반(axonal transport)를방해한다2,3,7.

암환자신경병증의평가(Evaluation)

말초신경병증은골수기능억제, 식욕부진, 오심, 구토, 점막염등

항암치료로인한다른부작용에비하여치료하는의료진의관심

과중요도로부터상대적으로낮은비중을차지하는경향이있으

며, 주기적인사정이이루어지지않아정확한사정과관찰이안

되는경우도있다. 실제일부연구에서는의료진이환자자신보다

말초신경병증을더낮게평가하는경향이있다고도하였다.

실제임상에서도말초신경병증으로불편감을호소하는암환자를

자주경험하게되고, 이로인해항암치료를중단하게되는경우

Management of peripheral neuropathy for cancer patients

지에서감각이상이나타난다. 증상은일시적이며약제투여중이

나투여직후에발생하고저온에노출되었을때잘나타난다. 그

러나곧저절로증상은소실된다. 약제의투여횟수가증가할수록

더자주나타나는경향을보인다. 만성증상은dose-limiting 부

작용으로약제의투여횟수가누적되면서나타난다. 약 16%에서

3-4도 신경독성을 경험한다4,9,10. 증상은 주로 사지에 이상감각

(dysesthesias) 또는 감각이상(paresthesias)가 나타나고, 항암

요법주기사이에지속되며누적양이증가할수록증상이심해진

다6. 점진적으로 감각 장애로 진행되며 감각-운동기능이상

(sensory-motor nerve dysfunction) 에 의해 옷의 단추 잠그

기, 글쓰기, 물건잡기등이어려워진다. 그외tendon reflex의

소실, spasm 등이나타날수있다. 만성독성은급성에비해천천

히나타나지만회복도매우느리다. 만성독성은특징적으로약

제에 대한 종양반응이 나타난 이후에 주로 나타난다10,11. 약제의

투여량이중앙값874 mg/m2 (10 cycle)일때3도이상의신경독

성이나타나며투여종료후약13주후부터서서히회복되기시

작한다8-10.

1) 항암제의의한말초신경병증의임상양상

CIPN의임상증상중운동, 감각신경과관련한증상으로손가락,

발가락의저림(tingling), 둔한 느낌 (numbness), 타는 듯한느

낌(burning), 찌르는느낌(stabbing), 쑤시는느낌(shooting), 따

끔거림 (pricking) 등이며, 감각의 저하나 소실은, 일차적으로

polyneuropathic 하며대개양측성이고원위부위, 신경축의길

이 의존적으로 초기에는 손가락, 발가락 부터 증상이 나타난다

환자는흔히손과발에흔히얇은스타킹이나장갑을착용하고있

는것처럼이상감각(stocking-glove “dying back”)에비유된다

4,5,7. (Fig. 1)

이러한 길이 의존적인 원위부 양상의 (length-dependent,

distal Pattern) 증상은신경병이악화되는경우에상방까지진

행된다. 결국이러한긴섬유는CIPN 약제에노출될수있는가

장넓은표면을갖고있어서보다많은독성을나타낸다. CIPN

다발성 신경병증이 발전하는 때 수근 골 증후군(carpal tunnel

syndrome) 발견되는중앙신경(median nerve)손상과같은단일

신경병은CIPN을다발성신경병으로더악화시킬수있다.

증상은통증을느낄정도로악화될수있고심부건반사(DTR) 상

실, 진동, 온도, 접촉, 위치감각의상실로진행될수있다. 이런

증상은급성으로나타나거나경미하거나일시적이며항암요법

을종료한후회복되기도하지만일부의경우더악화되는경우

도있으며 (‘coasting effect’) 비가역적인상태로남을수있다.

대개는사용한항암제의누적용량과관련이있다.

2) 신경병의기전Mechanisms of Neuropathy

- 항암제에의한신경독성의기전 - (Neurotoxicity Mechanisms of

Chemotherapeutic and Biologic Agents

말초신경내에서 운동신경축삭(motor axons)은 크고 수초화

(myelinated) 되어있는 반면 감각신경 과 자율신경의 축삭

(axon)은 대부분 작거나 비수초화(unmyelinated) 혹은 thinly

myelinated 되어있다.

앞서언급한데로신경원위부양상의(length-dependent, distal

Pattern) 증상은신경병이악화되는경우에상방까지진행된다.

즉, 가장긴섬유는항암약제에노출될수있는가장넓은표면을

갖고있어서보다많은독성을나타낸다3,7.

Taxanes과 vinca alkaloids계의 약물은 축삭손상을 유발하여

소위 축삭병변(axonopathy)를 초래하고 Platinum계는 배근신

경절(Dorsal root ganglion; DRG)에영향을준다. 작은신경섬

유는비교적초기에빈번하게영향을받는다7,12. 이들은재생능력

이작고잘손상되어항암제에의한신경병증이특히감각신경의

이상이 많은 이유로 설명된다. 작은 감각 혹은 말초감각신경의

세포체가배근신경절에위치하며이는혈액-뇌관문(blood brain

barrier)를보호하고바깥에존재하여손상받기쉽다3.

DRG는또한전신혈류에투과성이높은모세혈관이풍부하여혈

액내에독성물질에잘노출된다. 운동세포는항암제에의한신

경병증빈도가적기도하고상대적으로약물신경손상이덜심각

하며재생능력이좋아환자의근력과기능회복이잘된다. 자율신

14 Ik Yong Kim

Fig. 1. Symptoms of chemotherapy-induced peripheral neuropathy.5

History

•Personal history of neuropathy and CIPN from previous cancer treatment

• Personal and family history of hereditary neuropathy (patients with Charcot-Marie Tooth disease should avoid vincristine-based chemotherapy)

•Related comorbid conditions (e.g., diabetes, HIV, Guillain-Barre syndrome, CIDP, radiculopathy)

•Alcohol use

•Temporal profile: regimen dosage, duration, schedule,°∞coasting°± effects

•Symptoms

•Type: sensory, motor, or autonomic

•Distribution: distal symmetric or asymmetric

•Severity

•Pain assessment: BPI, LANSS, NPS

•Time course of CIPN, including onset and resolution of symptoms

•Treatment delays or discontinuation related to CIPN

Physical Examination

•Sensory assessment: light touch, vibration, proprioception, pin-prick, temperature

•Deep tendon reflex: presence, absence, diminishment

•Motor weakness

•Autonomic symptoms (e.g., constipation, orthostatic hypotension, urinary dysfunction, sexual dysfunction)

•Related musculoskeletal abnormalities (e.g., hammertoes, high or flattened arches)

Sample Questions for Patient

•Do you feel numbness or tingling in your hands or feet?

•Do you feel pain in your hands and feet? (Rate it on a scale of 0 to 10.)

•Do you feel like having gloves and stockings on?

•Do these sensations bother you? Are they getting worse?

•Do you feel weakness in your arms and legs?

•Do you drop things often?

•Have you fallen recently?

•Do you have difficulty walking or climbing stairs?

•Do these sensations interfere with your work or daily activities?

Examples of Functional Assessment Skill Tests

•Getting up and straight-line walking (observe gait and balance)

•Name writing

•Buttoning

•Timed pellet retrieval (for clinical trials)

•Pegboard test (for clinical trials)

Table 4. Key Points to Report During Clinical Assessment of CIPN

Abbreviations: BPI, Brief Pain Inventory; CIDP, chronic idiopathic demyelinating polyneuropathy; CIPN,

chemotherapy-induced peripheral neuropathy; LANSS, Leeds Assessment of Neuropathic Symptoms and Signs Pain Scale;NPS, Neuropathic Pain Scale.

17

Korean Journal of Clinical Oncology Summer 2011;Vol.7,NO.1:

Events (CTCAE) 이나WHO, ECOG의분류가일반적으로사용

되고있고13-15 최근에는NCI-CTCAE 보다CIPN에더민감하

고 정확한 Total Neuropathy Score(TNS)이 있다16. 문제는 각

척도의 범위가 달라 평가 방법 이나 신경병증으로 인한 증상이

매우주관적인면이있어이러한방법들만가지고환자가느끼는

증상을제대로파악하기에는한계가있다. (Table 5.)

한편, 연구에의하면의료진에의한사정은환자의말초신경병증

을저평가하는경향이있다고도한다. 실제의사나간호사들은

오심, 구토, 호중구감소증등의부작용은주의깊게관찰되는것

에반하여CIPN 말초신경병증은기타증상중하나로인식되는

경향이있어주기적인사정이이루어지지않는다고한다. 그러나

신경독성을제대로평가, 관리하지않으면, 치료에대한순응도

를떨어뜨리고, 삶의질및기능상태에심각한영향을미칠수

있다. 실제임상에서도치료도중말초신경병증으로불편감을호

소하는암환자를자주경험하게되고, 이로인해항암치료를중

단하게되는경우까지볼수있다.

예방 (Prevention)

항암제로 인한 말초신경병증의 표준적인 예방법이나 치료법은

아직 확립되어 있지 않고 다른 연구도 아직 근거가 불충분하다

17-19. 그이유는이들신경병의예방방법에관하여여러연구는

대부분소규모의환자를대상으로하였고전향적인연구결과가

적으며신경증상에대한객관적인평가가부적절하다는제한점

이다20-22. 현재소위신경보호제(Neuroprotector) 의여러전

향적인 연구가 진행 중이다23-25. 비교적 예방효과를 보이는

Vitamin E, Calcium/Magnesium, Amifostine, Glutamine,

Gglutathione, Glutamate 등을 사용한 몇몇 연구가 있다.

(Table 6.)

Management of peripheral neuropathy for cancer patients

까지볼수있다.

신경독성의치료가시작되기전에, 기본적인사정평가는중요하

므로반드시실행되고기록되어야한다12-14. 잠재적인위험요소를

갖는환자는CIPN의병세를긴급하게약화시키고CIPN의대부

분의경우가약물용량축적으로점진적으로나타나기때문에, 경

증의환자를조기에발견하여지속적으로감시하여야한다. 이러

한감시동안에다른신경병의원인도감별할수있다15,16. 또한,

일상적인임상평가의주요목표는환자가경험하고있는신경병

이과연검사가필요할것인지를결정하기위한것이다. 항암치

료도중신경독성이나신경증상을호소하는환자의기본적인평

가는 우선 환자의 호소가 신경병에 기인한 증상인지 암과 직접

관련된것인지또는, 치료나다른원인인지를파악한다. 그리고

불편을호소하는증상이과연검사를필요로하는것인지, 검사

한다면검사방법의선택, 증상의치료를위해어떤것을선택할

것인지마지막으로과연현재항암약제의용량변경이필요한지

혹은중단해야하는가에대한질문이다. Platinum 계약물을투

여하는 경우 CIPN 에 관한 주요 평가 항목들을 열거하였다.

(Table 4)

1. 신경생리학적검사(Neurophysiologic and other Objective Testing)

신경생리학적검사; electromyography(EMG), nerve

conduction studies (NCS), and quantitative sensory tests

(QST) 등이말초신경검사의객관적인정량검사등이다.

2. 임상사정과환자설문평가 (Clinical Assessment & Patient-Based

Evaluation)

신경병증의 평가사정방법으로는 NCI( National Cancer

Institute) 의 Common Terminology Criteria for Adverse

16 Ik Yong Kim

Scale Grade 1 Grade 2 Grade 3 Grade 4 Grade 5

WHO 9 Paresthesias and/ Severe paresthesias Intolerable Paralysis NA

or decreased and/or mild weakness paresthesias and/or

tendon reflexes marked motor loss

ECOG10 Decreased deep Absent deep tendon Disabling sensory Respiratory dysfunction NA

tendon reflexes, reflexes, severe loss, severe peripheral secondary to weakness,

mild paresthesias paresthesias or neuropathic pain, obstipation requiring

or constipation constipation, obstipation, severe surgery,

mild weakness weakness, bladder dysfunction paralysis confining

patient to bed/wheelchair

NCI-CTCAE (v3.0)11 Asymptomatic: Sensory alteration or Sensory alteration Disabling Death

Neuropathy-sensory loss of deep tendon Paresthesia (including or paresthesia

reflexes or paresthesia tingling), interfering with interfering with ADL

(including tingling) function but

but not interfering with not with ADL

function

Neuropathy-motor Asymptomatic, Symptomatic Weakness interfering with ADL: Lifet hreatening: Death

weakness by Weakness interfering bracing or assistance to walk Disabling (e.g., paralysis)

exam/testing only with function but indicated

not interfering with ADL

Ajani 8 Paresthesia, Mild objective Severe paresthesia, Complete NA

Sensory decreased deep abnormality, absence of moderate objective sensory loss, loss

tendon reflexes deep tendon reflexes, abnormality, of function

mild to moderate severe functional

functional abnormality abnormality

Motor Mild or transient Persistent moderate Unable to ambulate Complete paralysis NA

muscle weakness weakness but ambulatory

Table 5. Commonly Used Physician-Based Grading Scales for Evaluation of CIPN

Abbreviations: ADL, activities of daily living; CIPN, chemotherapy-induced peripheral neuropathy; NA, not applicable; NCICTCAE, National Cancer Institute Common Terminology Criteria for

Adverse Events.

Adapted from Stubblefield MD, Burstein HJ, Burton AW, Custodio, CM, Deng GE, Ho M et a.l NCCN Task Force Report: Management of Neuropathy in Cancer. J NCCN 2009; 7: S5;1-35

Drug Mechanism of Action Findings From Randomized Controlled Trials (Number of cases )

Agents with Positive Findings in Randomized Controlled Trials

Vitamin E Antioxidant/minimizes neuronal damage CIPN incidence and severity reduced (30-47)

CIPN severity reduced (81)

Ongoing trial: NCT00363129*

Ca++/Mg++ Facilitates Na channel function; binds oxalate CIPN incidence reduced (104)

(metabolite of oxaliplatin)

Glutamine Upregulation of nerve growth factor CIPN incidence reduced (86)

Glutathione Hampers accumulation of platinum adducts CIPN incidence reduced/trend towards reduction

in DRG (50-151)

N-acetylcysteine Antioxidant; increases blood concentrations of glutathione Incidence of grade 2-4 neuropathy reduced (14)

Oxcarbazepine Inhibits high-frequency firing of nerves; Neuropathy incidence reduced (32)

modulates ion channels

Xaliproden Non-peptide neurotrophic agent Shift of CIPN from grade 3 to grade 2 (649)

Ongoing trial: NCT00603577*

Agents With Negative Findings in Randomized Controlled Trials

Amifostine Detoxifies chemotherapy; facilitates DNA Not effective (66)

repair Improvement on NCI-CTC scale but not on patient questionnaire (72)

Nimodipine Calcium channel antagonist Not effective; randomized trial closed early (51)

Org 2766 Nerve growth factor family, Vibration perception maintained (55)

adrenocorticotrophic hormone analog Not effective (150-196)

rhuLIF Neuroprotective cytokine Not effective (117)

Additional Agents Being Tested in Ongoing Phase III Randomized Controlled Trials

Vitamin B12/B6 Essential for nerve function Ongoing trial: NCT00659269

Acetyl-L-carnitine Oxidation of free fatty acids/nerve regeneration New trial: NCT00775645*

Alpha lipoic acid Antioxidant Ongoing trial: NCT00705029*

Table 6. Current proposed Agents for Preventing CIPN

Abbreviations: CIPN, chemotherapy-induced peripheral neuropathy; DRG, dorsal root ganglion; NCI- CTC, National Cancer Institute Common Toxicity Criteria.

*ClinicalTrials.gov identification number

Adapted from Stubblefield MD, Burstein HJ, Burton AW, Custodio, CM, Deng GE, Ho M et a.l NCCN Task Force Report: Management of Neuropathy in Cancer. J NCCN 2009; 7: S5;1-35

17

Korean Journal of Clinical Oncology Summer 2011;Vol.7,NO.1:

Events (CTCAE) 이나WHO, ECOG의분류가일반적으로사용

되고있고13-15 최근에는NCI-CTCAE 보다CIPN에더민감하

고 정확한 Total Neuropathy Score(TNS)이 있다16. 문제는 각

척도의 범위가 달라 평가 방법 이나 신경병증으로 인한 증상이

매우주관적인면이있어이러한방법들만가지고환자가느끼는

증상을제대로파악하기에는한계가있다. (Table 5.)

한편, 연구에의하면의료진에의한사정은환자의말초신경병증

을저평가하는경향이있다고도한다. 실제의사나간호사들은

오심, 구토, 호중구감소증등의부작용은주의깊게관찰되는것

에반하여CIPN 말초신경병증은기타증상중하나로인식되는

경향이있어주기적인사정이이루어지지않는다고한다. 그러나

신경독성을제대로평가, 관리하지않으면, 치료에대한순응도

를떨어뜨리고, 삶의질및기능상태에심각한영향을미칠수

있다. 실제임상에서도치료도중말초신경병증으로불편감을호

소하는암환자를자주경험하게되고, 이로인해항암치료를중

단하게되는경우까지볼수있다.

예방 (Prevention)

항암제로 인한 말초신경병증의 표준적인 예방법이나 치료법은

아직 확립되어 있지 않고 다른 연구도 아직 근거가 불충분하다

17-19. 그이유는이들신경병의예방방법에관하여여러연구는

대부분소규모의환자를대상으로하였고전향적인연구결과가

적으며신경증상에대한객관적인평가가부적절하다는제한점

이다20-22. 현재소위신경보호제(Neuroprotector) 의여러전

향적인 연구가 진행 중이다23-25. 비교적 예방효과를 보이는

Vitamin E, Calcium/Magnesium, Amifostine, Glutamine,

Gglutathione, Glutamate 등을 사용한 몇몇 연구가 있다.

(Table 6.)

Management of peripheral neuropathy for cancer patients

까지볼수있다.

신경독성의치료가시작되기전에, 기본적인사정평가는중요하

므로반드시실행되고기록되어야한다12-14. 잠재적인위험요소를

갖는환자는CIPN의병세를긴급하게약화시키고CIPN의대부

분의경우가약물용량축적으로점진적으로나타나기때문에, 경

증의환자를조기에발견하여지속적으로감시하여야한다. 이러

한감시동안에다른신경병의원인도감별할수있다15,16. 또한,

일상적인임상평가의주요목표는환자가경험하고있는신경병

이과연검사가필요할것인지를결정하기위한것이다. 항암치

료도중신경독성이나신경증상을호소하는환자의기본적인평

가는 우선 환자의 호소가 신경병에 기인한 증상인지 암과 직접

관련된것인지또는, 치료나다른원인인지를파악한다. 그리고

불편을호소하는증상이과연검사를필요로하는것인지, 검사

한다면검사방법의선택, 증상의치료를위해어떤것을선택할

것인지마지막으로과연현재항암약제의용량변경이필요한지

혹은중단해야하는가에대한질문이다. Platinum 계약물을투

여하는 경우 CIPN 에 관한 주요 평가 항목들을 열거하였다.

(Table 4)

1. 신경생리학적검사(Neurophysiologic and other Objective Testing)

신경생리학적검사; electromyography(EMG), nerve

conduction studies (NCS), and quantitative sensory tests

(QST) 등이말초신경검사의객관적인정량검사등이다.

2. 임상사정과환자설문평가 (Clinical Assessment & Patient-Based

Evaluation)

신경병증의 평가사정방법으로는 NCI( National Cancer

Institute) 의 Common Terminology Criteria for Adverse

16 Ik Yong Kim

Scale Grade 1 Grade 2 Grade 3 Grade 4 Grade 5

WHO 9 Paresthesias and/ Severe paresthesias Intolerable Paralysis NA

or decreased and/or mild weakness paresthesias and/or

tendon reflexes marked motor loss

ECOG10 Decreased deep Absent deep tendon Disabling sensory Respiratory dysfunction NA

tendon reflexes, reflexes, severe loss, severe peripheral secondary to weakness,

mild paresthesias paresthesias or neuropathic pain, obstipation requiring

or constipation constipation, obstipation, severe surgery,

mild weakness weakness, bladder dysfunction paralysis confining

patient to bed/wheelchair

NCI-CTCAE (v3.0)11 Asymptomatic: Sensory alteration or Sensory alteration Disabling Death

Neuropathy-sensory loss of deep tendon Paresthesia (including or paresthesia

reflexes or paresthesia tingling), interfering with interfering with ADL

(including tingling) function but

but not interfering with not with ADL

function

Neuropathy-motor Asymptomatic, Symptomatic Weakness interfering with ADL: Lifet hreatening: Death

weakness by Weakness interfering bracing or assistance to walk Disabling (e.g., paralysis)

exam/testing only with function but indicated

not interfering with ADL

Ajani 8 Paresthesia, Mild objective Severe paresthesia, Complete NA

Sensory decreased deep abnormality, absence of moderate objective sensory loss, loss

tendon reflexes deep tendon reflexes, abnormality, of function

mild to moderate severe functional

functional abnormality abnormality

Motor Mild or transient Persistent moderate Unable to ambulate Complete paralysis NA

muscle weakness weakness but ambulatory

Table 5. Commonly Used Physician-Based Grading Scales for Evaluation of CIPN

Abbreviations: ADL, activities of daily living; CIPN, chemotherapy-induced peripheral neuropathy; NA, not applicable; NCICTCAE, National Cancer Institute Common Terminology Criteria for

Adverse Events.

Adapted from Stubblefield MD, Burstein HJ, Burton AW, Custodio, CM, Deng GE, Ho M et a.l NCCN Task Force Report: Management of Neuropathy in Cancer. J NCCN 2009; 7: S5;1-35

Drug Mechanism of Action Findings From Randomized Controlled Trials (Number of cases )

Agents with Positive Findings in Randomized Controlled Trials

Vitamin E Antioxidant/minimizes neuronal damage CIPN incidence and severity reduced (30-47)

CIPN severity reduced (81)

Ongoing trial: NCT00363129*

Ca++/Mg++ Facilitates Na channel function; binds oxalate CIPN incidence reduced (104)

(metabolite of oxaliplatin)

Glutamine Upregulation of nerve growth factor CIPN incidence reduced (86)

Glutathione Hampers accumulation of platinum adducts CIPN incidence reduced/trend towards reduction

in DRG (50-151)

N-acetylcysteine Antioxidant; increases blood concentrations of glutathione Incidence of grade 2-4 neuropathy reduced (14)

Oxcarbazepine Inhibits high-frequency firing of nerves; Neuropathy incidence reduced (32)

modulates ion channels

Xaliproden Non-peptide neurotrophic agent Shift of CIPN from grade 3 to grade 2 (649)

Ongoing trial: NCT00603577*

Agents With Negative Findings in Randomized Controlled Trials

Amifostine Detoxifies chemotherapy; facilitates DNA Not effective (66)

repair Improvement on NCI-CTC scale but not on patient questionnaire (72)

Nimodipine Calcium channel antagonist Not effective; randomized trial closed early (51)

Org 2766 Nerve growth factor family, Vibration perception maintained (55)

adrenocorticotrophic hormone analog Not effective (150-196)

rhuLIF Neuroprotective cytokine Not effective (117)

Additional Agents Being Tested in Ongoing Phase III Randomized Controlled Trials

Vitamin B12/B6 Essential for nerve function Ongoing trial: NCT00659269

Acetyl-L-carnitine Oxidation of free fatty acids/nerve regeneration New trial: NCT00775645*

Alpha lipoic acid Antioxidant Ongoing trial: NCT00705029*

Table 6. Current proposed Agents for Preventing CIPN

Abbreviations: CIPN, chemotherapy-induced peripheral neuropathy; DRG, dorsal root ganglion; NCI- CTC, National Cancer Institute Common Toxicity Criteria.

*ClinicalTrials.gov identification number

Adapted from Stubblefield MD, Burstein HJ, Burton AW, Custodio, CM, Deng GE, Ho M et a.l NCCN Task Force Report: Management of Neuropathy in Cancer. J NCCN 2009; 7: S5;1-35

19

Korean Journal of Clinical Oncology Summer 2011;Vol.7,NO.1:

나, 효과적으로조절되지않는경우를흔히경험하게된다31-33.

단독요법의약제가효과적인경우에는지속되어야하지만단독

약제로효과가없거나견디지못하는경우에, 다른약제를선택

하거나추가되어야한다. 또한, 종종많은경우에적절한진통제

가 추가로 필요하다. 두개의 무작위 이중맹검 연구에 결과처럼

338명의 환자 중 41명에서 gabapentin 단독군에 비하여

gabapentin과 opioid(morphine or oxycodone)를병용한군에

서부작용없이효과적인통증의감소를보여주고있다32-34.

CIPN에대한치료법이아직확립되지않은현시점에서약물사

용이금기가아니고부작용이문제가되지않는다면, 적극적으로

사용하는것을고려할수있다.

CIPN를 위한진통제에일반적인접근은임상의사의경험과효

과와 안전성에 대한 근거로 약제를 선택하는 것이다. 무엇보다

신경증의환자를조기에발견하여지속적으로감시하며심한경

우에는항암제의항암효과를늘염두하며약제를감량혹은중단

해야할지결정하여야한다. 실재, 항암제의용량을줄이거나치

료를연기또는중단하는경우도있으며이것은항암치료효과에

부정적인결과를가져올수있기때문이다. (Table 7.)

2) 비약물치료

신경전기자극치료Neurostimulation Therapy

전기신경자극치료척수자극 (spinal cord stimulation), 경피전

기신경자극Transcutaneous electrical nerve stimulation(TENS),

그외근적외광에너지(near-infrared photo energy) 를이용한

완화치료(anodyne therapy) 등이있다. 약물에효과가없는경

우나약물의금기인경우에보조치료로서고려해볼수는있으나

Management of peripheral neuropathy for cancer patients

치료 (Treatment)

암환자에서신경병증특히, 말초신경병증의치료는무엇보다약

물을포함한다양한원인유전질환, 자가면역질환, 감염, 영양결

핍 및 대사 불균형 등의 원인질환을 진단하고 정확히 인지하여

그에따라치료방법을결정하여야한다. 암과직접관련된신경

병 (Cancer-related neuropathy)은특히신경침윤된암종에서

수술그자체로신경병을완화시키는치료가되기도하며, 항암화

학치료, 방사선치료도 증상을 호전시켜 치료가 가능하다. 이들

신경독성에대한아직확실한예방법이나치료법은없다. 그러나

몇가지약제에서증상의호전이있다고보고하였다.

Oxaliplatin 의 CIPN 예방과 치료의 경우, Gamelin 등은20

calcium gluconate와 magnesium sulfate 를 각각 1 g씩

oxaliplatin 투여전/후에주입하였을때 3도이상의감각신경

이상이대조군(26%)에 비해현저히감소하고(7%) 치료 종료후

전체신경독성환자의비율도대조군(45%)에 비해적게발생하

였다(20%)고보고하였다. Grothey 등17(NCCTG trial N04C7)에

의하면보조항암약물요법으로 FOLFOX 투여 시 oxaliplatin투

여전/후로calcium gluconate와magnesium sulfate를각각1

g씩투여하였을때신경독성이대조군에비해신경독성의빈도

가낮았다NCI-CTCAE(P=0.038) OSS(p=0.01). Oxaliplatin은

특정한 Na＋channel에 작용하여 감각 및 운동신경sensory &

Motor 뉴론(neuron)의흥분도(excitability)를증가시킨다. 항경

련제인Carbamazepine은이에대한길항효과를나타내어신경

증상을 억제한다22. 그 외 항간질제인 gabapentin이나

venlafaxine을사용하기도한다. 또 Glutathione (GSH) 1,500

mg/m2을 oxaliplatin 투여전에 15분이상점적주입하였을때

신경독성이 대조군에 비해 적게 발생하였다는 보고도 있었다23.

Glutathione이neuroprotective agent로작용하는것으로추정

된다.

Tournigand 등은24 oxaliplatin의 신경독성을 줄이기 위한

OPTIMOX 1 연구에서2주간격으로12회연속투여하는기존의

투여방법군과 6회투여후 12회 oxaliplatin을제외한약제용법

regimen을 12회투여후다시6회투여하는방법군을비교하였

는데NCI-CTC 3도이상의신경독성이각각 54.4%, 48.7% 였

고7주기이후신경독성부작용이17.9%, 13.3%로oxaliplatin을

제외한 군에서 신경독성 부작용이 적게 나타났다고 하였다(P=.

12). Mattioli 등은25 oxaliplatin의 1회용량을45 mg/m2로줄여

서주1회2번을1주기로투여한바3도이상의신경독성이6%로

낮았다고 하였다. XELOX(Capcitabine/5-FU/Oxaliplatin) 투

여시oxaliplatin의용량을135/m2에서85/m2으로감량한바전

체신경독성의빈도는각각77%, 85% 였지만3/4도신경독성은

정량군에서14%가발생한반면감량군에서는1예도발생하지않

았다고하였다25.

요약하면치료효과를달성하기위해서는급성신경독성의경우

환자에게불편을줄수있지만일시적이며해가되지않고있는

합병증이라는설명을해주는것이중요하며찬곳에노출하지않

도록 주의를 당부해야 한다. 치료누적으로 인해 나타나는 만성

독성은치료주기를변경하거나신경조절제나신경보호제를투여

하면그빈도를낮출수있을것으로예상된다. 그러나신경독성

의증상의정도에따라다음주기의oxaliplatin의투여량을적절

하게조절하거나치료를중단해야하기도한다.

앞서Oxaliplatin 의CIPN 예방과치료처럼개개의약에대하여

일일히언급하는것이매우제한적이기때문에여기서는약물을

포함한다양한요인, 주로통증을호소하는CIPN (항암화학요법)

약물치료등의일반적인원칙을언급하고자한다.

1) CIPN 약물치료

현재까지 항암제 관련 신경병 CIPN 의 다양한 통증의 증상

(pain, paresthesia, dysesthesia, allodynia Table 2.) 에 비록

일부통증조절을위한약제들이개발되어왔지만명확하게증명

되어있는CIPN 의통증조절약제는없는실정이다.

치료약제는통증의정도를경감시키는등의증상적치료통증관

리이며현재통증치료제는항경련제Antiepileptic Drugs, 국소

마취제Local Anesthetics, 항우울제Antidepressants: 마약류

Opioids 등이있다26-33.

말초신경병증을조절하기위해사용되는약물들은Gabapentin

과Amitriptyline 이다27,28. 이들효과에대해서는아직명백히결

론이나지않은상태이다. 항경련제인Gabapentin의경우, 당

뇨병으로인한말초신경병증환자의신경병성통증을경감시키

고수면, 기분, 삶의질을향상시킨다는보고가있으나 CIPN의

무작위연구에서는위약과유의한차이가없는것으로나타났다

26-29.

항우울제인 Amitriptyline의 경우에도당뇨병으로인한말초신

경병증성통증에는효과가있는것으로되어있으나항암치료로

인한말초신경병증에는유의한효과가검증되지않았다.

임상에서는통증을유발하거나말초신경병증이발생하면증상완

화를 위해 삼환계 항우울제 (tricyclic antidepressant), 항경련

제anticonvulsants, 마약성진통제opioids 등을사용하고있으

18 Ik Yong Kim

Drug Starting Dose Titration Maximum DoseDuration of

Potential Side EffectsAdequate Trial

Duloxetine 20-30 mg/d No evidence that 120 mg/d 2 wk Nausea, xerostomia, constipation,

higher dose is more effective diarrhea

Gabapentin* 100-300 mg increase by 3600 mg 1-2 wk at max Somnolence, dizziness, GI

nightly or 100-300 mg 3 (depending on tolerated dose symptoms, mild edema,

100-300 mg 3 times/day, every absorption) cognitive impairment (elderly),

times/d 1-7 days exacerbation of gait problems

5% Lidocaine Maximum of 3 Non-applicable 3 patches 2 wk Rash/erythema

patch patches daily

Opioids 5-15 mg every Convert to longacting No ceiling effect 4-6 wk Constipation, nausea,

(oxycodone, 4 h after 1 wk, vomiting (self-limited),

morphine, titrate based on sedation, confusion,

methadone) breakthrough use respiratory depression

Pregabalin 25-50 mg 3 Increase by 50 mg/dose after 200 mg 3 times/d Unclear (likely Dizziness, somnolence,

times/d 1 wk 2-4 wk) xerostomia, edema,

blurred vision, decreased

concentration

Tramadol 50 mg 1-2/d Increase by 50-100 400 mg/d (100 4 wk Dizziness, constipation,

mg/d, individual mg 4 times/d); nausea, somnolence,

doses every 3-7 days elderly 300 mg/d orthostatic hypotension,

increased risk of seizure,

serotonin syndrome

Tricyclic Starting dose: Increase by 10-25 75-150 mg; may 6-8 wk; 1-2 wk Cardiovascular disease

antidepressants 10-25 mg mg every 3-7 days increase if blood at max dose (needs screening), anticholinergic

(amitriptyline,* nightly level of drug effects, interact with drugs metabolized

nortriptyline,* plus metabolite by cytochrome P450

desipramine) <100 ng/mL 2D6 (e.g., cimetidine, phenothiazine)

Table 7. Common Agents for Pain Management in Peripheral Neuropathy

*Negative results in randomized controlled clinical trials on chemotherapy-induced peripheral neuropathy

Adapted from Stubblefield MD, Burstein HJ, Burton AW, Custodio, CM, Deng GE, Ho M et a.l NCCN Task Force Report: Management of Neuropathy in Cancer. J NCCN 2009; 7: S5;1-35

19

Korean Journal of Clinical Oncology Summer 2011;Vol.7,NO.1:

나, 효과적으로조절되지않는경우를흔히경험하게된다31-33.

단독요법의약제가효과적인경우에는지속되어야하지만단독

약제로효과가없거나견디지못하는경우에, 다른약제를선택

하거나추가되어야한다. 또한, 종종많은경우에적절한진통제

가 추가로 필요하다. 두개의 무작위 이중맹검 연구에 결과처럼

338명의 환자 중 41명에서 gabapentin 단독군에 비하여

gabapentin과 opioid(morphine or oxycodone)를병용한군에

서부작용없이효과적인통증의감소를보여주고있다32-34.

CIPN에대한치료법이아직확립되지않은현시점에서약물사

용이금기가아니고부작용이문제가되지않는다면, 적극적으로

사용하는것을고려할수있다.

CIPN를 위한진통제에일반적인접근은임상의사의경험과효

과와 안전성에 대한 근거로 약제를 선택하는 것이다. 무엇보다

신경증의환자를조기에발견하여지속적으로감시하며심한경

우에는항암제의항암효과를늘염두하며약제를감량혹은중단

해야할지결정하여야한다. 실재, 항암제의용량을줄이거나치

료를연기또는중단하는경우도있으며이것은항암치료효과에

부정적인결과를가져올수있기때문이다. (Table 7.)

2) 비약물치료

신경전기자극치료Neurostimulation Therapy

전기신경자극치료척수자극 (spinal cord stimulation), 경피전

기신경자극Transcutaneous electrical nerve stimulation(TENS),

그외근적외광에너지(near-infrared photo energy) 를이용한

완화치료(anodyne therapy) 등이있다. 약물에효과가없는경

우나약물의금기인경우에보조치료로서고려해볼수는있으나

Management of peripheral neuropathy for cancer patients

치료 (Treatment)

암환자에서신경병증특히, 말초신경병증의치료는무엇보다약

물을포함한다양한원인유전질환, 자가면역질환, 감염, 영양결

핍 및 대사 불균형 등의 원인질환을 진단하고 정확히 인지하여

그에따라치료방법을결정하여야한다. 암과직접관련된신경

병 (Cancer-related neuropathy)은특히신경침윤된암종에서

수술그자체로신경병을완화시키는치료가되기도하며, 항암화

학치료, 방사선치료도 증상을 호전시켜 치료가 가능하다. 이들

신경독성에대한아직확실한예방법이나치료법은없다. 그러나

몇가지약제에서증상의호전이있다고보고하였다.

Oxaliplatin 의 CIPN 예방과 치료의 경우, Gamelin 등은20

calcium gluconate와 magnesium sulfate 를 각각 1 g씩

oxaliplatin 투여전/후에주입하였을때 3도이상의감각신경

이상이대조군(26%)에 비해현저히감소하고(7%) 치료 종료후

전체신경독성환자의비율도대조군(45%)에 비해적게발생하

였다(20%)고보고하였다. Grothey 등17(NCCTG trial N04C7)에

의하면보조항암약물요법으로 FOLFOX 투여 시 oxaliplatin투

여전/후로calcium gluconate와magnesium sulfate를각각1

g씩투여하였을때신경독성이대조군에비해신경독성의빈도

가낮았다NCI-CTCAE(P=0.038) OSS(p=0.01). Oxaliplatin은

특정한 Na＋channel에 작용하여 감각 및 운동신경sensory &

Motor 뉴론(neuron)의흥분도(excitability)를증가시킨다. 항경

련제인Carbamazepine은이에대한길항효과를나타내어신경

증상을 억제한다22. 그 외 항간질제인 gabapentin이나

venlafaxine을사용하기도한다. 또 Glutathione (GSH) 1,500

mg/m2을 oxaliplatin 투여전에 15분이상점적주입하였을때

신경독성이 대조군에 비해 적게 발생하였다는 보고도 있었다23.

Glutathione이neuroprotective agent로작용하는것으로추정

된다.

Tournigand 등은24 oxaliplatin의 신경독성을 줄이기 위한

OPTIMOX 1 연구에서2주간격으로12회연속투여하는기존의

투여방법군과 6회투여후 12회 oxaliplatin을제외한약제용법

regimen을 12회투여후다시6회투여하는방법군을비교하였

는데NCI-CTC 3도이상의신경독성이각각 54.4%, 48.7% 였

고7주기이후신경독성부작용이17.9%, 13.3%로oxaliplatin을

제외한 군에서 신경독성 부작용이 적게 나타났다고 하였다(P=.

12). Mattioli 등은25 oxaliplatin의 1회용량을45 mg/m2로줄여

서주1회2번을1주기로투여한바3도이상의신경독성이6%로

낮았다고 하였다. XELOX(Capcitabine/5-FU/Oxaliplatin) 투

여시oxaliplatin의용량을135/m2에서85/m2으로감량한바전

체신경독성의빈도는각각77%, 85% 였지만3/4도신경독성은

정량군에서14%가발생한반면감량군에서는1예도발생하지않

았다고하였다25.

요약하면치료효과를달성하기위해서는급성신경독성의경우

환자에게불편을줄수있지만일시적이며해가되지않고있는

합병증이라는설명을해주는것이중요하며찬곳에노출하지않

도록 주의를 당부해야 한다. 치료누적으로 인해 나타나는 만성

독성은치료주기를변경하거나신경조절제나신경보호제를투여

하면그빈도를낮출수있을것으로예상된다. 그러나신경독성

의증상의정도에따라다음주기의oxaliplatin의투여량을적절

하게조절하거나치료를중단해야하기도한다.

앞서Oxaliplatin 의CIPN 예방과치료처럼개개의약에대하여

일일히언급하는것이매우제한적이기때문에여기서는약물을

포함한다양한요인, 주로통증을호소하는CIPN (항암화학요법)

약물치료등의일반적인원칙을언급하고자한다.

1) CIPN 약물치료

현재까지 항암제 관련 신경병 CIPN 의 다양한 통증의 증상

(pain, paresthesia, dysesthesia, allodynia Table 2.) 에 비록

일부통증조절을위한약제들이개발되어왔지만명확하게증명

되어있는CIPN 의통증조절약제는없는실정이다.

치료약제는통증의정도를경감시키는등의증상적치료통증관

리이며현재통증치료제는항경련제Antiepileptic Drugs, 국소

마취제Local Anesthetics, 항우울제Antidepressants: 마약류

Opioids 등이있다26-33.

말초신경병증을조절하기위해사용되는약물들은Gabapentin

과Amitriptyline 이다27,28. 이들효과에대해서는아직명백히결

론이나지않은상태이다. 항경련제인Gabapentin의경우, 당

뇨병으로인한말초신경병증환자의신경병성통증을경감시키

고수면, 기분, 삶의질을향상시킨다는보고가있으나 CIPN의

무작위연구에서는위약과유의한차이가없는것으로나타났다

26-29.

항우울제인 Amitriptyline의 경우에도당뇨병으로인한말초신

경병증성통증에는효과가있는것으로되어있으나항암치료로

인한말초신경병증에는유의한효과가검증되지않았다.

임상에서는통증을유발하거나말초신경병증이발생하면증상완

화를 위해 삼환계 항우울제 (tricyclic antidepressant), 항경련

제anticonvulsants, 마약성진통제opioids 등을사용하고있으

18 Ik Yong Kim

Drug Starting Dose Titration Maximum DoseDuration of

Potential Side EffectsAdequate Trial

Duloxetine 20-30 mg/d No evidence that 120 mg/d 2 wk Nausea, xerostomia, constipation,

higher dose is more effective diarrhea

Gabapentin* 100-300 mg increase by 3600 mg 1-2 wk at max Somnolence, dizziness, GI

nightly or 100-300 mg 3 (depending on tolerated dose symptoms, mild edema,

100-300 mg 3 times/day, every absorption) cognitive impairment (elderly),

times/d 1-7 days exacerbation of gait problems

5% Lidocaine Maximum of 3 Non-applicable 3 patches 2 wk Rash/erythema

patch patches daily

Opioids 5-15 mg every Convert to longacting No ceiling effect 4-6 wk Constipation, nausea,

(oxycodone, 4 h after 1 wk, vomiting (self-limited),

morphine, titrate based on sedation, confusion,

methadone) breakthrough use respiratory depression

Pregabalin 25-50 mg 3 Increase by 50 mg/dose after 200 mg 3 times/d Unclear (likely Dizziness, somnolence,

times/d 1 wk 2-4 wk) xerostomia, edema,

blurred vision, decreased

concentration

Tramadol 50 mg 1-2/d Increase by 50-100 400 mg/d (100 4 wk Dizziness, constipation,

mg/d, individual mg 4 times/d); nausea, somnolence,

doses every 3-7 days elderly 300 mg/d orthostatic hypotension,

increased risk of seizure,

serotonin syndrome

Tricyclic Starting dose: Increase by 10-25 75-150 mg; may 6-8 wk; 1-2 wk Cardiovascular disease

antidepressants 10-25 mg mg every 3-7 days increase if blood at max dose (needs screening), anticholinergic

(amitriptyline,* nightly level of drug effects, interact with drugs metabolized

nortriptyline,* plus metabolite by cytochrome P450

desipramine) <100 ng/mL 2D6 (e.g., cimetidine, phenothiazine)

Table 7. Common Agents for Pain Management in Peripheral Neuropathy

*Negative results in randomized controlled clinical trials on chemotherapy-induced peripheral neuropathy

Adapted from Stubblefield MD, Burstein HJ, Burton AW, Custodio, CM, Deng GE, Ho M et a.l NCCN Task Force Report: Management of Neuropathy in Cancer. J NCCN 2009; 7: S5;1-35

21

Korean Journal of Clinical Oncology Summer 2011;Vol.7,NO.1:

magnesium salts to reduce oxaliplatin-related neurotoxicity. J Clin

Oncol 25:4028-9, 2007

19. Vajda FJ: Neuroprotection and neurodegenerative disease. J

Clin Neurosci 2002;9:4-8.

20. Gamelin L, Boisdron-Celle M, Delba R, et al: Prevention of

oxaliplatinrelated neurotoxicity by calcium and magnesium

infusions: A retrospective study of 161 patients receiving

oxaliplatin combined with 5-fluorouracil and leucovorin for

advanced colorectal cancer. Clin Cancer Res 2004;10:4055-61.

21. Knijn N, Tol J, Koopman M, et al: The effect of prophylactic

calcium and magnesium infusions on the incidence of

neurotoxicity and clinical outcome of oxaliplatin-based systemic

treatment in advanced colorectal cancer patients. Eur J Cancer

2011;47:369-74.

22. Lersch C, Schmelz R, Eckel F, Erdmann J, Mayr M, Schulte-

Frohlinde E, et al. Prevention of oxaliplatin-induced peripheral

sensory neuropathy by carbamazepine in patients with advanced

colorectal cancer. Clin Colorectal Cancer 2002;2:54-8.

23. Cascinu S, Catalano V, Cordella L, Labianca R, Giordani P,

Baldelli AM, et al. Neuroprotective effect of reduced glutathione

on oxaliplatin-based chemotherapy in advanced colorectal cancer:

a randomized, double-blind, placebo-controlled trial. J Clin Oncol

2002;20:3478-83.

24. Tournigand C, Cervantes A, Figer A, Lledo G, Flesch M, Buyse

M, et al. OPTIMOX1: a randomized study of FOLFOX4 or

FOLFOX7 with oxaliplatin in a stop-and-Go fashion in advanced

colorectal cancer--a GERCOR study. J Clin Oncol 2006;24:394-400.

25. Mattioli R, Massacesi C, Recchia F, Marcucci F, Cappelletti C,

Imperatori L, et al. High activity and reduced neurotoxicity of bi-

fractionated oxaliplatin plus 5-fluorouracil/leucovorin for elderly

patients with advanced colorectal cancer. Ann Oncol

2005;16:1147-51.

26. Hammack JE, Michalak JC, Loprinzi CL, et al. Phase III

evaluation of nortriptyline for alleviation of symptoms of

cisplatinum- induced peripheral neuropathy. Pain 2002;98:195-203.

27. Kautio AL, Haanpaa M, Saarto T, Kalso E. Amitriptyline in the

treatment of chemotherapy-induced neuropathic symptoms. J

Pain Symptom Manage 2008;35:31-9.

28. Rao RD, Flynn PJ, Sloan JA, et al. Efficacy of lamotrigine in the

management of chemotherapy-induced peripheral neuropathy: a

phase 3 randomized, double-blind, placebo-controlled trial, N01C3.

Cancer 2008;112:2802-8.

29. Rao RD, Michalak JC, Sloan JA, et al. Efficacy of gabapentin in

the management of chemotherapy-induced peripheral

neuropathy: a phase 3 randomized, double-blind, placebo-

controlled, crossover trial (N00C3). Cancer 2007;110:2110-8.

30. Barton D, Wos E, Qin R, et al. A randomized controlled trial

evaluating a topical treatment for chemotherapy-induced

neuropathy: NCCTG trial N06CA [abstract]. J Clin Oncol

2009;27(Suppl 15S):Abstract 9531.

31. Durand JP, Deplanque G, Gorent J, et al. Efficacy of

venlafaxine for the prevention and relief of acute neurotoxicity of

oxaliplatin: results of EFFOX, a randomized, double-blinded,

placebo-controlled prospective study [abstract]. J Clin Oncol

2009;27(Suppl 15S):Abstract 9533.

32. Backonja M, Beydoun A, Edwards KR, et al. Gabapentin for

the symptomatic treatment of painful neuropathy in patients with

diabetes mellitus: a randomized controlled trial. JAMA

1998;280:1831-6.

33. Gilron I, Bailey JM, Tu D, et al. Morphine, gabapentin, or their

combination for neuropathic pain. N Engl J Med 2005;352:1324-34.

34. Wernicke JF, Pritchett YL, D’Souza DN, et al. A randomized

controlled trial of duloxetine in diabetic peripheral neuropathic pain.

Neurology 2006;67:1411-20.

35. Melzack R, Wall PD. Pain mechanisms: a new theory. Science

1965;150:971-9.

36. Cruccu G, Aziz TZ, Garcia-Larrea L, et al. EFNS guidelines on

neurostimulation therapy for neuropathic pain. Eur J Neurol

2007;14:952-70.

37. Daousi C, Benbow SJ, MacFarlane IA. Electrical spinal cord

stimulation in the long-term treatment of chronic painful diabetic

neuropathy. Diabet Med 2005;22:393-8.

38. Nicholas PK, Kemppainen JK, Canaval GE, et al. Symptom

management and self-care for peripheral neuropathy in HIV/ AIDS.

AIDS Care 2007;19:179-89.

39. Haythornthwaite JA, Benrud-Larson LM. Psychological

assessment and treatment of patients with neuropathic pain. Curr

Pain Headache Rep 2001;5:124-9.

Management of peripheral neuropathy for cancer patients

아직근거가부족하다35-37.

3) 보완 및 대체요법 (Complementary and Alternative Medicine

(CAM) Therapy

설문조사에따르면실제신경병을앓고있는40% 이상의환자는

보완 및 완화치료를 받고 있다고 한다. 일반적으로 권고하지는

않으나 비타민대량투여요법 (Megavitamins), 침술

(acupuncture), 마시지 (massage), 명상 바이오피드백

biofeedback, 식이용법Dietary supplement 와온요법이있다

38.7 -38. 이러한비약물중재는아직그효과가입증되지않았으나,

통증을완화시키는효과가있어특히, 찬것에노출되면말초신

경병증으로인한증상이더악화되는특징이있는Oxaliplatin

의경우온요법을시행하는경우일시적인효과가있다고한다.

당뇨병환자의말초신경병증에치료법으로적용하고있는유산

소운동, 스트레칭등의효과는CIPN 연구에서는찾아볼수없다.

따라서 CIPN을위한비약물적중재를개발하고효과를검증하

는연구들도활발하게진행되어야할것이다.

결 론

신경병, 또는말초신경병의정의는뇌및척수로연결되는모든

운동, 감각, 자율신경등말초신경의손상이나기능이상으로부터

발생하는상황을일컫는다. 암환자에서신경병의결과는더심각

하여 이는 삶의 질을 떨어뜨리고 일상생활을 방해하거나, 무력

감, 장애를초래하고결국잠재적으로는생존기간에도영향을미

칠수있다. 암성신경병의원인과특성, 기전은다양하다. 암관

련신경병의일반적인연구나항암화학요법으로인해발생하는

말초신경병증(CIPN)의. 현재까지의 연구는 대부분 소규모이며

근거중심의예방과치료효과를평가하기는어려운실정이다아

직도경험적인치료가많아향후좀더많은환자를대상으로한

무작위전향적연구. 로 효과적인약제, 중재방법을정립한다면

암환자의삶의질을향상시키는데도움이될것으로기대된다.

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21

Korean Journal of Clinical Oncology Summer 2011;Vol.7,NO.1:

magnesium salts to reduce oxaliplatin-related neurotoxicity. J Clin

Oncol 25:4028-9, 2007

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oxaliplatinrelated neurotoxicity by calcium and magnesium

infusions: A retrospective study of 161 patients receiving

oxaliplatin combined with 5-fluorouracil and leucovorin for

advanced colorectal cancer. Clin Cancer Res 2004;10:4055-61.

21. Knijn N, Tol J, Koopman M, et al: The effect of prophylactic

calcium and magnesium infusions on the incidence of

neurotoxicity and clinical outcome of oxaliplatin-based systemic

treatment in advanced colorectal cancer patients. Eur J Cancer

2011;47:369-74.

22. Lersch C, Schmelz R, Eckel F, Erdmann J, Mayr M, Schulte-

Frohlinde E, et al. Prevention of oxaliplatin-induced peripheral

sensory neuropathy by carbamazepine in patients with advanced

colorectal cancer. Clin Colorectal Cancer 2002;2:54-8.

23. Cascinu S, Catalano V, Cordella L, Labianca R, Giordani P,

Baldelli AM, et al. Neuroprotective effect of reduced glutathione

on oxaliplatin-based chemotherapy in advanced colorectal cancer:

a randomized, double-blind, placebo-controlled trial. J Clin Oncol

2002;20:3478-83.

24. Tournigand C, Cervantes A, Figer A, Lledo G, Flesch M, Buyse

M, et al. OPTIMOX1: a randomized study of FOLFOX4 or

FOLFOX7 with oxaliplatin in a stop-and-Go fashion in advanced

colorectal cancer--a GERCOR study. J Clin Oncol 2006;24:394-400.

25. Mattioli R, Massacesi C, Recchia F, Marcucci F, Cappelletti C,

Imperatori L, et al. High activity and reduced neurotoxicity of bi-

fractionated oxaliplatin plus 5-fluorouracil/leucovorin for elderly

patients with advanced colorectal cancer. Ann Oncol

2005;16:1147-51.

26. Hammack JE, Michalak JC, Loprinzi CL, et al. Phase III

evaluation of nortriptyline for alleviation of symptoms of

cisplatinum- induced peripheral neuropathy. Pain 2002;98:195-203.

27. Kautio AL, Haanpaa M, Saarto T, Kalso E. Amitriptyline in the

treatment of chemotherapy-induced neuropathic symptoms. J

Pain Symptom Manage 2008;35:31-9.

28. Rao RD, Flynn PJ, Sloan JA, et al. Efficacy of lamotrigine in the

management of chemotherapy-induced peripheral neuropathy: a

phase 3 randomized, double-blind, placebo-controlled trial, N01C3.

Cancer 2008;112:2802-8.

29. Rao RD, Michalak JC, Sloan JA, et al. Efficacy of gabapentin in

the management of chemotherapy-induced peripheral

neuropathy: a phase 3 randomized, double-blind, placebo-

controlled, crossover trial (N00C3). Cancer 2007;110:2110-8.

30. Barton D, Wos E, Qin R, et al. A randomized controlled trial

evaluating a topical treatment for chemotherapy-induced

neuropathy: NCCTG trial N06CA [abstract]. J Clin Oncol

2009;27(Suppl 15S):Abstract 9531.

31. Durand JP, Deplanque G, Gorent J, et al. Efficacy of

venlafaxine for the prevention and relief of acute neurotoxicity of

oxaliplatin: results of EFFOX, a randomized, double-blinded,

placebo-controlled prospective study [abstract]. J Clin Oncol

2009;27(Suppl 15S):Abstract 9533.

32. Backonja M, Beydoun A, Edwards KR, et al. Gabapentin for

the symptomatic treatment of painful neuropathy in patients with

diabetes mellitus: a randomized controlled trial. JAMA

1998;280:1831-6.

33. Gilron I, Bailey JM, Tu D, et al. Morphine, gabapentin, or their

combination for neuropathic pain. N Engl J Med 2005;352:1324-34.

34. Wernicke JF, Pritchett YL, D’Souza DN, et al. A randomized

controlled trial of duloxetine in diabetic peripheral neuropathic pain.

Neurology 2006;67:1411-20.

35. Melzack R, Wall PD. Pain mechanisms: a new theory. Science

1965;150:971-9.

36. Cruccu G, Aziz TZ, Garcia-Larrea L, et al. EFNS guidelines on

neurostimulation therapy for neuropathic pain. Eur J Neurol

2007;14:952-70.

37. Daousi C, Benbow SJ, MacFarlane IA. Electrical spinal cord

stimulation in the long-term treatment of chronic painful diabetic

neuropathy. Diabet Med 2005;22:393-8.

38. Nicholas PK, Kemppainen JK, Canaval GE, et al. Symptom

management and self-care for peripheral neuropathy in HIV/ AIDS.

AIDS Care 2007;19:179-89.

39. Haythornthwaite JA, Benrud-Larson LM. Psychological

assessment and treatment of patients with neuropathic pain. Curr

Pain Headache Rep 2001;5:124-9.

Management of peripheral neuropathy for cancer patients

아직근거가부족하다35-37.

3) 보완 및 대체요법 (Complementary and Alternative Medicine

(CAM) Therapy

설문조사에따르면실제신경병을앓고있는40% 이상의환자는

보완 및 완화치료를 받고 있다고 한다. 일반적으로 권고하지는

않으나 비타민대량투여요법 (Megavitamins), 침술

(acupuncture), 마시지 (massage), 명상 바이오피드백

biofeedback, 식이용법Dietary supplement 와온요법이있다

38.7 -38. 이러한비약물중재는아직그효과가입증되지않았으나,

통증을완화시키는효과가있어특히, 찬것에노출되면말초신

경병증으로인한증상이더악화되는특징이있는Oxaliplatin

의경우온요법을시행하는경우일시적인효과가있다고한다.

당뇨병환자의말초신경병증에치료법으로적용하고있는유산

소운동, 스트레칭등의효과는CIPN 연구에서는찾아볼수없다.

따라서 CIPN을위한비약물적중재를개발하고효과를검증하

는연구들도활발하게진행되어야할것이다.

결 론

신경병, 또는말초신경병의정의는뇌및척수로연결되는모든

운동, 감각, 자율신경등말초신경의손상이나기능이상으로부터

발생하는상황을일컫는다. 암환자에서신경병의결과는더심각

하여 이는 삶의 질을 떨어뜨리고 일상생활을 방해하거나, 무력

감, 장애를초래하고결국잠재적으로는생존기간에도영향을미

칠수있다. 암성신경병의원인과특성, 기전은다양하다. 암관

련신경병의일반적인연구나항암화학요법으로인해발생하는

말초신경병증(CIPN)의. 현재까지의 연구는 대부분 소규모이며

근거중심의예방과치료효과를평가하기는어려운실정이다아

직도경험적인치료가많아향후좀더많은환자를대상으로한

무작위전향적연구. 로 효과적인약제, 중재방법을정립한다면

암환자의삶의질을향상시키는데도움이될것으로기대된다.

REFERENCES

1. Hausheer FH, Schilsky RL, Bain S, et al. Diagnosis,

management, and evaluation of chemotherapy-induced peripheral

neuropathy. Semin Oncol 2006; 33:15-49.

2. Stubblefield MD, Burstein HJ, Burton AW, Custodio, CM, Deng

GE, Ho M et a.l NCCN Task Force Report:Management of

Neuropathy in Cancer. J NCCN 2009; 7: S5;1-35

3. Park SB, Krishnan AV, Lin CS, et al. Mechanisms underlying

chemotherapy-induced neurotoxicity and the potential for

neuroprotective strategies. Curr Med Chem 2008;15:3081-94.

4. Park SB, Goldstein D, Lin CS, et al. Acute abnormalities of

sensory nerve function associated with oxaliplatin-induced

neurotoxicity. J Clin Oncol 2009;27:1243-9

5. Simpson DA, Tagliati M, Gonzales-Duarte A, Mongello S.

Neurologic manifestations. In: Mildvan D, ed. International Atlas of

AIDS, 4th edition. Hoboken, NJ: Current Medicine Group LLC; 2007;

6. Becouarn Y, Ychou M, Ducreux M, et al. Phase II trial of

oxaliplatin as first-line chemotherapy in metastatic colorectal

cancer patients. Digestive Group of French Federation of Cancer

Centers. J Clin Oncol 1998; 16:2739-44.

7. Windebank AJ, Grisold W. Chemotherapy-induced neuropathy.

J Peripher Nerv Syst 2008;13:27-46.

8. Park SB, Lin CS, Krishnan AV, et al: Oxaliplatin-induced

neurotoxicity: Changes in axonal excitability precede development

of neuropathy. Brain 2009;132:2712-23.

9. Nikcevich DA, Grothey A, Sloan JA, et al. Effect of intravenous

calcium and magnesium (IV CaMg) on oxaliplatin-induced sensory

neurotoxicity (sNT) in adjuvant colon cancer: results of the phase

III placebo-controlled, double-blind NCCTG trial N04C7 [abstract]. J

Clin Oncol 2008;26(Suppl 18S):Abstract 4009.

10. Haller DG. Safety of oxaliplatin in the treatment of colorectal

cancer. Oncology (Williston Park) 2000;14(12 Suppl 11):15-20.

11. de Gramont A, Figer A, Seymour M, Homerin M, Hmissi A,

Cassidy J, et al. Leucovorin and fluorouracil with or without

oxaliplatin as first-line treatment in advanced colorectal cancer. J

Clin Oncol 2000;18:2938-47.

12. Ajani JA, Welch SR, Raber MN, et al. Comprehensive criteria for

assessing therapy-induced toxicity. Cancer Invest 1990;8:147- 59.

13. Miller AB, Hoogstraten B, Staquet M, Winkler A. Reporting

results of cancer treatment. Cancer 1981;47:207-14.

14. Oken MM, Creech RH, Tormey DC, et al. Toxicity and

response criteria of the Eastern Cooperative Oncology Group. Am

J Clin Oncol 1982;5:649-55.

15. National Cancer Institute. National Cancer Institute-Common

Terminology Criteria for Adverse Events (NCI-CTCAE), version 3.0.

Available at: http://ctep.cancer.gov/protocolDevelopment/

electronic_applications/ docs/ctcaev3.pdf. Accessed July 8, 2009.

16. Cavaletti G, Frigeni B, Lanzani F, et al. The Total Neuropathy

Score as an assessment tool for grading the course of

chemotherapy induced peripheral neurotoxicity: comparison with

the National Cancer Institute-Common Toxicity Scale. J Peripher

Nerv Syst 2007;12:210-5.

17. Grothey A, Nikcevich DA, Sloan JA, et al: Intravenous calcium

and magnesium for oxaliplatin-induced sensory neurotoxicity in

adjuvant colon cancer: NCCTG N04C7. J Clin Oncol 2011;29:421-7.

18. Hochster HS, Grothey A, Childs BH: Use of calcium and

20 Ik Yong Kim

서 론

유방암은 일차적인 치료로 수술을 가장 먼저 고려하며, 비교적

암발생초기부터원격전이가동반되는특성으로항암화학요법도

활발하게병행되고있다. 유방암에서방사선치료의역할은크게

두부분으로수술후국소재발을낮추기위한보조치료와, 전이

암환자의증상완화를위한고식적목적의방사선치료이며, 주

로보조적방사선치료의역할및의의를살펴보고자한다.

1. 유방보존수술후방사선치료

유방암 환자의 수술적 방법은 환자 및 종양의 특성을 고려하여

근치적절제술(M, mastectomy) 혹은 유방보존술(BCS, breast

conserving surgery)을선택한다. 유방보존치료를위해서는반

드시완전절제가필요하며수술후국소재발의위험을낮추기위

해서는 보조적 방사선치료가 필수적이다 (2011 NCCN

Guideline Category I). 대단위3상임상시험의meta-analysis

에서보조적방사선치료는국소재발을유의하게낮출뿐만아니

라국소재발로인한치사율도25% 정도감소시켜주었다(1).

통상적인방사선치료방법은그림 1에서보여주듯이전유방방

사선치료 (WBI, whole breast irradiation)이며일일 1.8 - 2.0

Gy 의방사선량을주5회, 총45 Gy - 50.4 Gy 방사선치료를시

행하고있다.

WBI은 약 1개월이상의통원치료기간이소요되며장거리이동

시간이필요한환자에게는이러한불편함이유방보존수술의걸

림돌이라하겠다. 대단위임상연구의장기간의추적결과에따라

여전히모든환자에서BCS 후에는방사선치료를반드시고려하

도록권고하고있으나일부BCS 후국소재발의위험이매우낮

다고 여겨지는 환자에서 방사선치료를 제외 시키고자 CALGB

9343 임상연구가 시행 되었으며 이에 대한 10년 추적결과는

2010년ASCO 연례보고에발표된바있다(2). 저자들은70세이

상의 고령의 환자에서 2cm 미만의 종양의 크기에 호르몬 억제

치료를시행할경우방사선치료를제외시킬수있음을조심스럽

게제안하였다(표1).

상피내암환자에서유방보존수술후방사선치료는잔존유방의

재발의위험을50-60% 낮추어주며, 방사선치료를시행하지않

책임저자 : 안성자

519-763, 전남화순군화순읍일심리 160 화순전남대학교병원방사선종양학과

Tel: 061-379-7200 Fax: 061-379-7249 E-mail: ahnsja@chonnam.ac.kr

접수일 : 2011년 5월 23일 ; 게재승인일 : 2011년 6월 20일

23

R E V I E W A R T I C L E

Radiation Therapy for the Oncologist in Breast Cancer

Radiation Therapy for the Oncologist in Breast Cancer

유방암의방사선치료

전남의대방사선종양학과 안성자

Chonnam National University Medical School

Sung-Ja Ahn, M.D.

그림 1.유방보존 수술 후 접사면 (tangential beam) 조사방법을

사용하는 전유방 방사선치료

Outcomes (10 years) Tam. + RT Tam. Alone(n=317) (n=319) p

lpsilateral Breast Tumor Recurrence 6 ( 2%) 27 ( 9%) .0001

Ultimate Mastectomy 4 ( 2%) 10 ( 4%) .1779

Second Primary Cancer 36 (12%) 33 ( 9%) .7268

Distant Metastasis 21 ( 5%) 16 ( 5%) .461

Death 157 (33%) 166 (33%) .8045

Breast cancer 12 ( 3%) 8 ( 2%) .4115

표 1.Adjuvant Tamoxifen with or without in Patients 70 Years

of Age with Stage I ER-Positive Breast Cancer: Efficacy

22 Ik Yong Kim

Management of peripheral neuropathy for cancer

patients

Department of Surgery, Yonsei University Wonju College of Medicine Wonju, Korea

Ik Yong Kim, M.D.

Abstract

Neuropathy in cancer patients or patients with peripheral neuropathy is a common and often difficult and

debilitating complication of cancer or the treatment-related. Chemotherapy-Induced Peripheral Neuropathy (CIPN)

is most widely reported and has been the focus of research efforts among the various types of neuropathies in

cancer patients. Platinum-based drugs, such as cisplatin and oxaliplatin, are well-known for inducing chronic

sensory neuropathies, but their acute and motor neurotoxicities are less well characterized.

Multidisciplinary team was charged with the review the literature and discussion intervention strategies currently

available to patients as well as areas that require research efforts for the possible prevention, diagnosis, and

management of peripheral neuropathy.

Effective management of neuropathy or CIPN depends on early diagnosis and an understanding of its underlying

causes in the individual patient. Patients with neuropathic pain (NP) are also challenging to manage and evidence-

based clinical recommendations for pharmacologic management are needed.

The objectives of this article are to discuss: Systematic literature reviews, randomized clinical trials, and existing

guidelines were evaluated in prevention, assessment and treatment of the various types of neuropathies in cancer

patients

Correspondence : Ik Yong Kim, M.D.

Department of Surgery, Yonsei University Wonju College of Medicine, 162 Ilsan-dong, Wonju, Korea. 220-701

Tel: 82-33-741-0573, Fax: 82-33-744-6604 E-mail: iykim@yonsei.ac.kr

Received : May 23, 2011 ; Accepted : Jun 20, 2011