Korean J. Oriental Physiology & Pathology 28(5):565~570, 2014 항암화학요법으로인한말초신경병증환자의한방치험 1 례 이지혜 1,3 박혜림 1,2 이혜윤 1,2 조민경 1,2 홍미나 1 한창우 1,2 최준용 1,3 박성하 1,2 권정남 1,2 이인 1,2 홍진우 1,2 김소연 1,3* 1 : 부산대학교한방병원한방내과, 2 : 부산대학교한의학전문대학원한의학과, 3 : 한의과학과 Case Report of Chemotherapy Induced Peripheral Neuropathy Treated with Korean M edicine Ji Hye Lee 1,3, Hye Lim Park 1,2, Hye Yun Lee 1,2, Min Kyoung Cho 1,2, Mi Na Hong 1, Chang Woo Han 1,2, Jun Yong Choi 1,3, Seong Ha Park 1,2, Jung Nam Kwon 1,2, In Lee 1,2, Jin Woo Hong 1,2, So Yeon Kim 1,3 * 1 : Department of Korean Internal Medicine, Pusan National University Korean Medicine Hospital, 2 : Department of Korean Medicine, School of Korean Medicine, Pusan National University, 3 : Department of Korean Medical Science, School of Korean Medicine, Pusan National University The purpose of this study is to report a clinical case of a patient with CIPN (Chemotherapy Induced Peripheral Neuropathy) successfully treated with Korean medicine interventions including acupuncture, herbal medicine and moxibustion. The patient is a female with CIPN who was diagnosed with ascending colon cancer and suffering from paresthesia of extremities after chemotherapy of platinum compounds. The patient was treated mainly with electroacupuncture (Ex-LE 10), indirect moxibustion and herbal medicine (Ucha-Shinki-hwan granule). The clinical outcomes were measured by NCI CTCAE grade, EORTC QLQ-C30 (CIPN20) scale and patient s assessment of symptoms. In this case, the NCI CTCAE grade was improved from II to I. The scores of global health status and functional scale in QLQ-C30 were increased and symptom scale was decreased. Especially, this case shows a noticeable decrease in sensory scale in QLQ-CIPN20. In patient s general assessment, the scale was changed from 10 to 5. Korean medical interventions including acupuncture, herbal medicine and moxibustion could potentially be an effective for CIPN if further researches are conducted. keywords : CIPN, cancer, acupuncture, oxaliplatin, herbal medicine, moxibustion 서론 항암화학요법은암의주된치료방법중의하나이나, 이러한치료는암세포뿐만아니라정상세포에도영향을주어환자에게전신부작용을유발할수있다. 그중말초신경병증은항암화학요법을받는환자의 30-40% 에서발생하며, 영향인자는항암제의누적용량, 강도, 치료기간, 다른신경독성약제와의동시투여, 환자의연령, 당뇨, 알코올남용과같은이전병력등이다 1). 증상은말초신경계의손상으로인한신경병증성통증, 감각저하등이주를이루며, 이는항암환자의삶의질을저하시키는심각한요인이되고있다. 항경련제, 마약성진통제등의약물요법과수기치료, 운동요법등의비약물요법이치료법으로사용되고있지만그효과에대한근거는부족한실정이다 2,3). 항암화학요법후발생한말초신경병증의한의학적치료에대한보고중침치료에대해서는증례및임상연구가있으나치료방법과평가방법등이다양하여아직까지그효과에대한근거는미흡하다 4-8). 한약치료에대한연구로는동물모델에서석창포, 감국, 백과, 패모가증상개선효과를보였으며 9-12), 임상연구에서보양환오탕, 시호가용골모려탕, 우차신기환, 계지가출부탕의통증개선혹은신경보호효과가보고된바있다 13-16). 기타치료로약침및봉독크림을통해증상이호전된연구결과들이있었다 17,18). 실제임상에서는복합치료가적용되고있는만큼본논문에서는침, 뜸, 한약치료를병행하여항암화학요법시행후발생한말초신경병증이호전된사례를보고하고자한다. 환자의상태및항암제의종류에따라증상과예후가다양한만큼향후 * Corresponding author So Yeon Kim, School of Korean Medicine, Pusan National University, Mulgeum-eup, Yangsan city, Gyeongsangnamdo, Korea E-mail : omdksy@gmail.com Tel : +82-55-360-5954 Received : 2014/09/03 Revised : 2014/10/14 Accepted : 2014/10/21 c The Korean Society of Korean Pathology, The Korean Society of Korean Physiology pissn 1738-7698 eissn 2288-2529 Available online at www.hantopic.com
566 J. H. Lee et al 여러치료방법이제시되고이에대한근거가확보된다면암환 자의삶의질을높이는데에많은도움이될것이다. 증 례 1. 환자정보 : 47 세, 여자, 163cm, 57.9kg 2 진단명 Ascending colon cancer, CIPN (Chemotherapy-induced peripheral neuropathy) 3. 주소 : Paresthesia (hand and foot), Fatigue 4. 현병력 : 2012 년 10 월 16 일 ascending colon cancer (pt4an1am0) 진단하에 2012 년 10 월 23 일근치적대장절제술 (Laparoscopic extended right hemicolorectomy) 을시행하였 으며, 2012 년 11 월 21 일부터 2013 년 5 월 10 일까지 12 차에걸 쳐 FOLFOX (Oxaliplatin + Leucovorin + 5-FU) 보조항암화 학요법을받았다. 이후수족부의저림심화되고피로감지속되 어 2013 년 6 월 7 일 OO 대학교한방병원에입원하여 6 월 21 에 퇴원하였다. 진단및항암화학요법과관련한자세한환자정보 는 Table 1 에기재하였다. Table 1. Characteristics of case diagnosis and interventions Age (Sex) 47 (female) Impression Ascending colon cancer Tumor stage pt4an1am0 Purpose of chemotherapy Adjuvant chemotherapy Every 2weeks for 12 cycles - Exolatin(Oxaliplatin) (85mg/m2) D1 Drugs used for chemotherapy - Leucovorin (200mg/m2) D1-5-FU(push) (400mg/m2) D1 5-FU(infusion) (1200mg/m2) D1~2 Duration of chemotherapy 2012/11/21 ~ 2013/5/10 Use of analgesics 2013/4/25~29, 2013/5/11~15 - Neurontin(Gabapentin) 100mg P123 Relevant comorbidities No Once a day for fifteen days Acupuncture - Manual acupuncture at GB20, CV12, CV10, ST25, TE5, HT7, KI3, ST36 - Electro acupuncture at Ex-LE10 Korean Medicine interventions Moxa Herbmed 5. 과거력 : Uterine myoma (2011 년 ) 6. 가족력 : Diabetes mellitus ( 형제 ) 7. 초진시검사소견 1) 四診소견 - 수면 : 양호 - 식욕 : 보통 Once a day for fifteen days - indirect moxibustion at TE4, TE5, LR3, GB41, KI1 Medication of Boshinzi (Uchashinkihwan granule) three times a day, after each meal for fourteen days - 소화 : 보통 - 한열 : 惡寒, 手足冷 - 땀 : 보통 - 대변 : 1일 1회, 보통변 - 소변 : 양호 - 기타 : 鼻漏, 鼻塞 - 면색 : 黑 - 맥진 : 沈, 弱 - 설진 : 舌質淡, 薄白苔 2) 주소증 (1) 수족저림및이상감각 : 본환자는항암화학요법 10회이후부터양측수족부에저림및냉감이발생하였다. 이후점차증상의정도가심해져 11회와 12회항암화학요법이후에는각각 5일간항경련제인 neurontin을매일 300 mg 이상복용하였으나증상의호전은없었다. 본원입원시수족부의증상은 NRS 3~4 정도이고특히수지와족지말단부에찌릿한통전감이있어물건을집기가불편하며 5분이상의보행이힘든상태였다. (2) 피로 : 항암치료이후부터평소대비 50% 정도피로감증가하였으며, 본원입원시에는기력저하로활동을기피하는편이었다. 8. 치료및처치 1) 침치료입원기간동안 1일 1회총15회의침치료를시행하였으며각혈자리에 0.5~1.0 cm 깊이로자입 ( 동방침구제작소, 0.20 mm x 0.30 mm. stainless) 하여득기후, 20분간유침하였다. 풍지, 중완, 하완, 천추, 외관, 신문, 태계, 족삼리, 태충, 팔풍에자침하였으며양측팔풍에는전침 (slow and fast mode, 20/100Hz) 을적용하였다. 2) 뜸치료입원기간동안 1일 1회총15회의간접애주구를적용하였다. 양지, 외관, 태충, 임읍, 용천, 족근부에강화미니뜸 ( 이화당, 한국 ) 중강도微 ( 약 50 ) 인것을사용하여시술하였다. 1회시술시각혈위에 3장씩시행하였다. 3) 한약치료입원기간동안 1일 3회총14일간보신지과립 ( 쯔무라제약, 일본 ) 1포를식후 30분에투약하였다. 보신지과립 1포의원료약품분량은택사 3 mg, 우슬 3 mg, 지황 5 mg, 정제부자 1 mg, 차전자피 3 mg, 계피 1 mg, 목단피 3 mg, 복령 3 mg, 산약 3 mg, 산수유 3 mg 이다. 9. 평가방법 1) Global Assessment (G/A) 입원당시환자가느꼈던통증및불편감을 10 으로, 통증및불편감이없는상태를 0 으로가정했을때, 치료이후환자가자각하는증상의정도를숫자로표현하도록하였다. 2) NCI CTCAE (Ver. 4.03) National Cancer Institute (NCI) 에서정의한 Common
J. H. Lee et al 567 Toxicity Criteria for Adverse Event (CTCAE) 의하위항목중말초신경병증관련항목은 Grade I~IV로구분되어 I: Mild symptoms or asymptomic, II: Moderate ; limiting instrumental ADLs(Activities of Daily Living), III: Severe ; limiting self-care ADLs, IV: Life-threatening consequence 로정의되어있다. Grade I 은의학적처치를필요로하지않는수준이나, Grade II 이상에서는의학적처치를권장하고있다 19). 3) EORTC QLQ-C30 European Organization for Research and Treatment of Cancer (EORTC) 에서개발한 Quality of Life Questionnaire-Core 30 (QLQ-C30) 은암환자의삶의질을파악하는도구로전반적인삶의질 (General health status), 기능영역 (Functional scale), 증상영역 (Symptom scale) 의 3가지하위영역으로이루어져있다. 점수는지침에따라 100점을만점으로환산하여삶의질영역과기능영역점수가높을수록, 증상영역점수가낮을수록삶의질이좋은것을의미한다. 4) EORTC QLQ-CIPN20 Quality of life questionnaire chemotherapy-induced peripheral neuropathy (CIPN20) 은 QLQ-C30의하위모듈로 Postma 등20에의해개발되었고한국어로번역한것을사용하였다. 이도구는총 20개의문항으로, 운동영역 8문항, 감각영역 9문항, 자율신경영역 3문항으로구성되어있으며, 점수는지침에따라 100점을만점으로환산하여점수가높을수록삶의질이낮은것을의미한다. 10. 치료결과 1) 증상및 G/A 치료 4일째에수장부저림이 G/A 10에서 G/A 7로감소하였으나수지와족지말단부의찌릿한느낌과족부의냉감은지속되고있었다. 치료 7일째에는안정시저림이많이감소되었으나, 스마트폰구동등의수지동작시에말단부가여전히저리다고하였다. 치료 9일째에는손바닥과발바닥을만졌을때느껴지던둔하고먹먹한느낌이완화되고수족부모두저림증상이 G/A 6으로감소하였다. 치료 12일째에는오래보행하거나기립했을때발바닥에느껴지던냉감과부종감이경감되었다고하였고, 치료 15일째인퇴원일에는수족부의저림증상이 G/A 5 정도로감소하였다. 치료기간에따른 G/A 변화는 Fig. 1에그래프로나타내었다. 2) CTCAE 치료전 Paresthesia( 이상감각 ) 항목에서 Grade II(Moderate symptoms; limiting instrumental ADLs) 정도의증상을호소하였으나, 치료후 Grade I(mild symptoms) 으로호전되었다. 3) EORTC QLQ-C30 전반적인삶의질점수와기능영역점수가증가하고, 증상영역의점수가감소하여환자의삶의질이향상되었음을보여주었다. 치료전후의항목별점수는 Table 2에기재하였다 4) EORTC QLQ-CIPN20 감각영역, 운동영역, 자율신경계영역의점수가모두감소하 여말초신경병증증상이호전되었음을보여주었다. 치료전후 의항목별점수는 Table 2 에기재하였다. Fig. 1. Change of Global Assessment (G/A) Table 2. NCI CTCAE grade and EORTC QLQ score berfore and after QLQ-C30 QLQ-CIPN20 Contents of Sensory scale (in QLQ-CIPN20) Before After NCI CTCAE Grade II Grade I Global health status 66.67 83.33 Functional scale 68.89 93.33 Symptom scale 20.51 0.00 Sensory scale 48.15 14.81 Motor scale 4.17 0.00 Autonomic scale 16.67 0.00 Tingling (hands) 3 2 Tingling (feet) 3 2 Numbness (hands) 2 1 Numbness (feet) 3 1 Pain (hands) 3 2 Pain (feet) 3 2 The scales of QLQ-C30 and QLQ-CIPN20 measures range in score from 0 to 100. The contents of sensory scale are scored 1 to 4. A high score represents a higher response level. 고 찰 항암화학요법으로인한말초신경병증은 platinum compounds, taxanes, vinka alkaloids, bortezomib, thalidomide 등의항암제에의해유발되는것으로알려져있으 며, 증상의정도와예후는약물의종류, 용량, 투여기간등에따 라다양하다 21. 본연구의환자는 platinum 계열의 oxaliplatin 이포함된항암화학요법을받았는데, oxaliplatin 은약제투여 중또는직후에발생하여 1 주이내에증상이소실되는급성말 초신경병증과치료종료이후장기간지속되는만성말초신경병 증을유발할수있다. 급성신경병증의경우증상의정도는심 하지않으며화학요법치료를받은환자의 60~90% 에서발생한 다. 만성증상은 oxaliplatin 의누적사용량이높을수록나타나기 쉬우며증상은기온저하에의해악화되는수족부위이상감각이 나감각저하가주를이루고발생률은 10~18% 이다 22). 말초신경손상의객관적인정량검사로는 Electromyography (EMG), Nerve Conduction Studies (NCS), Quantitative Sensory Tests (QST) 등의신경생리학적
568 J. H. Lee et al 검사가있으나 23) 이러한검사들은항암치료도중항암제용량조절및중단을결정하기위해필요하다고판단될때주로사용하는것으로본연구의증례에서는항암치료가거의종료되는시점에증상이발현되어별도로시행되지않았다. 항암치료로인한말초신경병증에대한평가는주로환자설문평가로이루어지는데, 본증례에서는일반적으로사용되고있는 NCI-CTCAE의분류와 EORTC QLQ-CIPN20를적용하였다. Ellen M. 등의연구 24) 에서신경독성이있는항암화학요법을받은환자의 QLQ-CIPN20 평균점수는감각영역 20.17점, 운동영역 14.33점, 자율신경계영역이 3.49점이었으며, 항암화학요법을받은대장암환자를대상으로한국내연구 25) 에서는감각영역점수가 32.7점, 운동영역 16.12점, 자율신경영역 22.88점이었다. 본증례에서치료전감각영역점수는 48.15점으로기존연구의평균점수보다높은반면운동영역의점수는 4.17점으로낮았다. 이는 oxaliplatin 에의해유발되는신경병증은운동신경증상은거의없고, 자율신경계증상은간헐적으로나타나며, 이상감각이나감각저하등의감각신경증상이주를이룬다는기존연구결과 25) 와일치한다. Oxaliplatin에의한만성말초신경병증의자연경과는평균적으로항암화학요법종료후 13주가지나서서서히회복되기시작하며 10% 의환자에서 2년이상증상이지속되기도한다 22). 그러나본증례의환자는 2주간의치료로 NCI-CTCAE(Gr II I) 및 EORTC QLQ-CIPN20( 감각영역 48.15 14.81점 ) 상조기회복을보였다. 경과판정은항목별점수변화가 5-10점인경우약간의변화, 10-20점은중간정도, 20점초과는상당한변화로분류되는데 26), 감각영역에서 30점이상의경감을보여임상적으로의미있는호전이라할수있다. 퇴원후외래진료를통해경과를관찰한결과, 남아있던증상이서서히경감되어 4개월뒤에는거의소실되고족부저림만간헐적으로남아있었다. 항암화학요법으로인한말초신경병증의치료는약물요법으로칼슘과마그네슘, 비타민 E, 삼환계항우울제, 항경련제, 아세틸-L-카르니틴 (Acetyl-L-carnitine), 글루타민 (Glutamin), 글루타티온 (Glutathione), 마약성진통제등이있고, 비약물요법으로침, 보조기, 운동요법, Pulsed infrared light therapy(pilt), 경피신경전기자극 (Transcutaneous nerve stimulation, TENS), 캡사이신연고, 수기치료등이있지만실제암환자를대상으로한연구가부족하여근거가제한적인실정이다 2,28). 항암화학요법으로인한말초신경병증의침치료에대한임상연구는증례 4-6) 와대조군연구 6-8) 가보고된바있으며, 주로곡지, 외관, 합곡, 족삼리, 태충, 팔풍등의혈위가사용되었다. 대체로침치료가증상개선효과를보였고, cobamamide나 neurotropin 등의신경보호치료를받은대조군보다증상의개선률이높게나타나기도했으나 6,7), vitamin B1/B6치료및위약대조군과유의한차이가없다는결과 8) 도있었다. 전침을적용한임상연구에서는족임읍-양릉천, 태충-음릉천, 합곡-곡지, 후계- 소해에전침을적용한그룹에서증상이호전되었으나위약대조 군과유의한차이는없었다 8). 본증례에서는통증발생인접부위인팔풍혈에전침자극을가함으로써척수의신경전달인자조절을통한진통효과를기대하였다. 특히저빈도와고빈도의교대전류가내인성오피오이드시스템에서신경전달물질인 endomorphin과 dynorphin의상보작용을유도하여통각억제효과를나타낸다는연구결과 29) 에따라 20Hz와 100Hz의교대전류를적용하였다. 그러나동물모델연구에서 paclitaxel 치료후발생한신경병증에 100Hz 보다 10Hz에서통증억제효과가높았고 30), 신경병증성통증에고주파보다저주파의진통효과및지속시간이길다는보고 31) 가있어향후치료시주파수를변경해볼필요가있다. 환자가이상감각중특히냉감을호소하여족저부에간접애주구를적용한것도치료에도움을준것으로여겨진다. 기존연구에서단독뜸치료효과에대한보고는없으나관원, 또는증상발현부위인접혈위에뜸치료가병행된경우들은있다 32,33). 또한본환자는수족저림과피로감외에도만성비염으로인한콧물, 전신부종감등을호소하며脈沈弱, 舌淡하여腎氣虛寒으로보고우차신기환과립제인보신지 ( 쯔무라제약, 일본 ) 를투약하였다. 항암치료로인한말초신경병증의한약치료중에는우차신기환에대한연구가가장활발히진행되었는데 9-16), oxaliplatin 투여직후또는병행하여우차신기환을복용한군이무처치또는 Ca 2+ /Mg + 처치대조군보다신경병증발생률이현저히낮았다 14,15). 또한 paclitaxel이나 carboplatin 치료를받은암환자에서 vitamin B12단독투여군보다우차신기환병행투여군에서 6주후신경병증발생률이유의하게낮았다 16). 한편우차신기환이말초통각수용체의민감도를낮추고혈관확장등을통한말초순환개선으로진통효과를유도하며, 신경축삭손상예방과신경돌기재생및시냅스형성보조로손상된말초신경의회복을돕는다는작용기전에대한연구도있었다 13). 이상본증례에서항암화학요법으로인한말초신경병증에한약치료, 침치료, 팔풍혈전침, 뜸치료가수족부의저림및이상감각증상을호전시키는효과가있음을확인하였으며고찰결과침치료와우차신기환관련연구에서그근거를확인할수있었다. 더불어안전성만확보된다면향후연구에서이미신경손상이진행된항암치료종료후가아닌, 항암치료중에한의학적치료를병행함으로써더큰효과를기대해볼수있을것이다. 결론 항암치료로인한말초신경병증으로손발저림및이상감각을호소하던환자를대상으로팔풍혈전침위주의침치료, 우차신기환을비롯한한약치료, 하지부위뜸치료시행후증상의호전을확인하였기에이를보고하는바이다. 감사의글 본연구는 2013년도부산대학교병원임상연구비지원으로이루어졌음.
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