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1 SMN SURGICAL METABOLISM AND NUTRITION Vol. 8, No. 2, December, 2017 pissn , eissn ORIGINAL ARTICLE 위암환자에서 XELOX 항암화학요법의순응도와영양인자들과의상관관계 박상현ㆍ송금종ㆍ손명원ㆍ한선욱ㆍ배상호ㆍ김성용ㆍ백무준ㆍ이문수 순천향대학교천안병원외과 Association of Nutrition Status-Related Indices and XELOX Chemotherapy Compliance in Gastric Cancer Patients Sang Hyun Park, M.D., Geum Jong Song, M.D., Myoung Won Son, M.D., Ph.D., Sun Wook Han, M.D., Sang Ho Bae, M.D., Ph.D., Sung Yong Kim, M.D., Ph.D., Moo Jun Baek, M.D., Ph.D., Moon Soo Lee, M.D., Ph.D. Department of Surgery, Soonchunhyang University Cheonan Hospital, Cheonan, Korea Purpose: Cancer-associated malnutrition is common in gastric cancer patients and affects their response to treatment. This study evaluated pre-operative and pre-chemotherapy nutritional status-related indices associated with compliance in post-operation state gastric cancer patients receiving chemotherapy. Materials and Methods: We retrospectively reviewed medical records of patients with gastric cancer undergoing curative D2 resection between August 2014 and July A total of 51 patients who underwent adjuvant chemotherapy with a regimen of capecitabine and oxaliplatin (XELOX) were screened. Nutritional status assessment included body weight (BW), body mass index (BMI), serum albumin, serum total protein, hemoglobin, and total lymphocyte count (TLC). Results: Twenty-six patients had stage II gastric cancer, and 25 patients had stage Ⅲ gastric cancer according to the guidelines of the American Joint Committee on Cancer. Eighty-two percent of patients completed their chemotherapy according to the therapy protocol. However, 49% of patients were subjected to drug dose reduction, and 18% of patients needed to cease therapy. We found that pre-chemotherapy serum albumin level was significantly associated with completion of chemotherapy (P=0.043), and there was no significant relationship of BW, BMI, serum total protein, hemoglobin, and TLC with compliance of chemotherapy. Conclusion: Our study results suggest that patients with a low serum albumin level are highly susceptible to discontinuation of chemotherapy. Thus, serum albumin concentration could be used as a predictor of successful completion of chemotherapy before starting treatment. (Surg Metab Nutr 2017;8:36-40) Key Words: Nutrition, Gastric cancer, Chemotherapy 서론 위암은전세계에서네번째로흔히진단되는암종일뿐만아니라, 암관련사망의세번째주요원인이다.[1] 최근들어내시경을통한위암의조기발견과수술술기및종합적인치료에있어커다란진보가있었음에도불구하고위암환자의장 기생존율은여전히높지않다.[2] 진행성위암환자의경우대부분수술후보조항암화학요법 (Adjuvant chemotherapy) 을시행하게되는데, 위절제술이후의보조항암화학요법은식욕부진, 구강건조, 미각의변화, 구역, 설사, 변비및피로감을유발하여결국체중감소및영양실조로이어진다.[3] 이러한암관련영양실조는많은위암환 Received October 2, Accepted November 21, Correspondence to: Moon Soo Lee, Department of Surgery, Soonchunhyang University Cheonan Hospital, 31 Soonchunhyang 6gil, Dongnam-gu, Cheonan 31151, Korea Tel: , Fax: , msslee@schmc.ac.kr CC This is an open access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Copyrights c The Korean Society of Surgical Metabolism and Nutrition

2 Sang Hyun Park, et al: Association of Nutrition Status and Chemotherapy Compliance 37 자에서발생하며, 이는환자의삶의질뿐만아니라항암치료에대한반응에도영향을미치는것으로알려져있다.[4,5] 암환자의영양실조는치료에대한반응을감소시키고, 치료와관련된여러부작용들로인해약제의투여농도를낮추거나때로는항암치료를지속할수없게만들기도한다.[6,7] 이에본연구에서는위암으로수술을시행한후보조항암화학요법을받은환자들에서각각수술전과항암화학요법을시작하기전에측정한영양상태를나타내는지표들중항암화학 을중단하거나용량을감소하여시행한군에서각각의영양인자들과의연관성이있는지분석하였다. 항암요법의부작용정도는 Common Terminology Criteria for Adverse Events (CTCAE, version 4.0) 에따라분류하였으며, 통계분석은 SPSS 18.0 for windows (SPSS Inc., Chicago, IL, USA) 를사용하였다. 독립표본 T 검정을통해유의성을검증하였으며, P값이 0.05 미만인경우를통계적으로유의한것으로판정하였다. 요법의순응도와연관이있는인자들이있는지알아보고자하 였다. 결과 대상및방법 2014년 8월부터 2016년 7월까지순천향대학교천안병원위장관외과에서위암으로근치적절제술을받은환자중 American Joint Committee on Cancer (AJCC) 의위암병기분류법제 7 판에따라,[8] 보조항암화학요법의대상이되는 2기와 3기의환자들을선별하여 Capecitabine과 Oxaliplatin (XELOX) 의병용요법을시행한총 51명의환자를대상으로하였다. 모든환자들은나이, 성별, 수술후재건술의방법, TNM병기, 그리고수술부터보조항암화학요법을시작하기까지의기간등을전자의무기록을통하여조회하였으며, 수술전과첫번째보조항암화학요법을시작하기전에영양인자들을측정하였다. 환자들의영양상태를반영하는영양인자로서는체중, 신체질량지수 (body mass index, BMI), 혈청알부민수치, 총단백질, 혈색소, 그리고총림프구수를조사하였으며, 보조항암화학요법 51명의대상환자의평균연령은 60세 (34 79세) 이었으며, 그중남자가 42명 (82%), 여자가 9명 (18%) 이었다. 위원위부절제술을시행한환자는 37명 (72.5%) 이었으며, 그중 15명은위-십이지장문합술을시행하였고, 22명은위-공장문합술을시행하였다. 14명 (27.5%) 의환자는위전절제술을시행하였으며모두 uncut-roux 식도-공장문합술로재건하였다. 환자들의병기는 2기가 26명 (51%), 3기가 25명 (49%) 이었으며, 수술부터보조항암화학요법을시작하기까지의평균기간은 37.1일 (26 50일) 이었다 (Table 1). 42명 (82%) 의환자가치료계획에따라총 8차례의보조항암화학요법을모두완료하였다. 그러나전체환자중 49% 인 25 명의환자들이치료도중약제의투여농도를감량하였으며, 그중 9명 (18%) 은결국치료를중단하였다. 약제의투여농도를감량한 25명의환자중감량횟수는 1회가 20명이었고, 2회감량한경우도 5명이있었다. 감량을결정한보조항암화학요법 의주기는두번째주기가 8명 (32%) 으로가장많았으며, 세번째, 네번째주기가각각 6명 (24%), 5명 (20%) 순이었다. 투여 Table 1. Clinical characteristics of patients Characteristics No (%) (n=51) Sex Male 42 (82.4) Female 9 (17.6) Age (years) Median 60.0 Range TNM stage IIA 11 (21.6) IIB 15 (29.4) IIIA 5 (9.8) IIIB 15 (29.4) IIIC 5 (9.8) Type of reconstruction Interval from operation to chemotherapy (days) Billroth I gastroduodenostomy 15 (29.4) Billroth II gastrojejunostomy 22 (43.1) Uncut-Roux-en-Y reconstruction 14 (27.5) Median 37.1 Range Table 2. Causes of dose reduction and interruption during chemotherapy Causes Dose reduction (N=25) Interruption (N=9) Nausea/vomiting Grade Grade Diarrhea Grade Grade 3 4 Fatigue Grade Grade Neurotoxicity Grade Grade 3 4 Acute kidney injury Grade Grade Hematologic toxicity Grade 1 2 Grade 3 4 3

3 38 Surgical Metabolism and Nutrition Vol. 8, No. 2, 2017 농도를감량하게된원인은오심과구토증상이가장흔하였고, 그외에설사, 신경병증, 그리고피로감등의증상이있었다. 또한보조항암화학요법을중단한원인은 CTCAE grade 3 이상의오심과구토, 피로감등의전신조건의악화가가장많았으며, grade 3의급성신기능이상, 호중구감소증 (grade 3) 과혈소판감소증 (grade 4) 등의혈액학적독성반응을보인경우가있었다 (Table 2). 전체환자중표준용량을투여한군과농도를감량하여투여한군에서수술전과항암치료시작전의영양인자를각각비교하였을때, 수술전의총림프구수가두군간에유의한차이를보였으며 (P<0.042), 치료시작전의총림프구수역시차이를보였으나유의한결과를나타내지는못하였다 (P<0.062) (Table 3). 또한, 항암치료시작전의혈청알부민수치가보조항암화학요법을모두완료한군에서그렇지못한군에비해유의하게높은결과를보였다 (P<0.021). 그밖에체중, 신체질량 지수 (body mass index, BMI), 총단백질, 혈색소, 그리고총림프구수는보조항암화학요법의완료여부와는유의한상관관계를보이지않았다 (Table 4). 고찰 위암은수술을통한근치적절제가가장우선되는치료법으로알려져있다. 그러나진행성위암에있어서위절제술후의보조항암화학요법은위암치료의중요한부분이되고있으며, 대다수의위암환자는치료중에영양실조를경험하게된다.[7] 여러연구결과에따르면암환자의약 40 80% 정도가영양실조를경험하게되며이는전신상태의악화및생존율의감소와관련이있다고알려져있다.[9,10] 또한, 암환자의수술전영양상태는수술후의합병증, 회복및예후등에영향을미치는것으로알려져있으며수술전에영양실조가있었던환자에 Table 3. Univariate analysis of nutritional status related indices for dose reduction Variables Standard dose (N=26) Dose reduction (N=25) P-value Body weight (kg) Preoperative 64.21± ± Pre-chemotherapy 60.81± ± Body mass index (kg/m 2 ) Preoperative 22.76± ± Pre-chemotherapy 21.56± ± Serum albumin (g/dl) Preoperative 4.16± ± Pre-chemotherapy 3.87± ± Total protein (g/dl) Preoperative 6.86± ± Pre-chemotherapy 6.47± ± Hemoglobin (g/dl) Preoperative 13.53± ± Pre-chemotherapy 11.68± ± Total lymphocyte count (count/mm 3 ) Preoperative 2,328.46±1, ,841.60± Pre-chemotherapy 2,203.46± ,796.64± Values are presented as mean±standard deviation. Table 4. Univariate analysis of nutritional status related indices for completeness Variables Completion (N=42) Interruption (N=9) P-value Body weight (kg) Preoperative 62.95± ± Pre-chemotherapy 58.84± ± Body mass index (kg/m 2 ) Preoperative 23.02± ± Pre-chemotherapy 21.55± ± Serum albumin (g/dl) Preoperative 4.05± ± Pre-chemotherapy 3.91± ± Total protein (g/dl) Preoperative 6.71± ± Pre-chemotherapy 6.56± ± Hemoglobin (g/dl) Preoperative 13.89± ± Pre-chemotherapy 11.75± ± Total lymphocyte count (count/mm 3 ) Preoperative 2,112.14± ,985.56± Pre-chemotherapy 2,001.81± ,014.44± Values are presented as mean±standard deviation.

4 Sang Hyun Park, et al: Association of Nutrition Status and Chemotherapy Compliance 39 서수술후이환율과사망률이증가하는것으로보고되었다.[11-13] 따라서수술전환자들의영양결핍상태를파악하고그에따른적절한영양공급을시행하는것은수술후합병증과사망률을감소시켜장기적인예후의향상을가져올수있다.[14] 환자들의영양상태를평가하는방법에는 Nutritional risk screening 2002 (NRS-2002), Malnutrition Universal Screening Tool (MUST), Subjective Global Assessment (SGA), 그리고 Patient Generated-Subjective Global Assessment (PG-SGA) 와같은표준화된영양검색도구나영양평가도구를이용하는방법이있으며, 체중, 신체질량지수와같은신체계측정보를활용하거나혈액, 체액등을이용한생화학검사등이이용된다. 영양상태를파악하는지표로사용되는생화학검사에는혈청알부민, 총단백질, 혈색소, 총림프구수등이있으며, 본연구에서도이들을영양인자로선별하여조사하였다. 신체질량지수와혈청알부민수치가수술환자에있어서수술후회복과재원기간, 그리고생존율등에영향을주는예측인자로활용될수있다는보고가있으며,[15] Lien 등 [16] 은위분문부암환자에서수술전혈청알부민수치가 3.5 g/dl이하인군이그렇지않은군에비하여수술시종양의완전절제율이낮고이환율이높으며, 5년생존율역시유의하게낮음을보고하였다. 혈색소와총단백질또한다른영양인자들과마찬가지로위암환자들이대조군에비해유의하게낮아져있음을확인할수있다.[17] 영양결핍이있는소화기암환자들에게수술전에시행한적절한영양공급은총림프구수를현저하게증가시킴으로써수술후예후를개선시킨다는결과를보고하기도하여면역기능을반영하는영양인자로서의역할을시사하였다.[18] 이처럼환자들의영양상태를반영하는여러인자들이수술후합병증발생과치료결과, 예후, 그리고장기적인생존율에영향을미친다는연구들은상당수진행되고그결과가보고되었다. 그러나, 이러한영양인자들이수술후보조항암화학요법을시행하는환자들의치료순응도와치료에대한반응에어떠한영향을미치는지는아직명확히밝혀진바가없다. Seo 등 [7] 은위암으로위절제술을받은환자에서혈청알부민등의영양인자가항암요법의부작용발생과상관관계가높다고보고하였으며, Arrieta 등 [19] 은 paclitaxel과 cisplatin으로치료받은폐암환자에서 Subjective Global Assessment (SGA) 와혈청알부민수치가항암화학요법으로유발된부작용과관련이있다고보고하였다. 전이된대장암환자에서도심각한영양결핍은항암화학요법의독성을증가시키고생존율을감소시킨 다는연구가있다.[20] 항암화학요법과영양상태를반영하는인자들과의상관관계를조사하는연구에서도항암치료에따른부작용과독성의발생에대하여주로보고하고있다. 본연구에서는위암으로수술을시행후보조항암화학요법을받는환자를대상으로영양인자들이직접적인치료순응도에미치는상관관계를연구하고자하였다는점에서중요한의의가있다. 다만, 본연구의한계점으로는대상표본이되는환자의숫자가적고후향적인연구라는점과영양인자외에고령, 합병증유무, 절제술형태등항암화학요법에영향을줄수있는다른분석요인 (variables) 의수가많지않다는점, 그리고단변량분석으로결론을내리기에는통계적한계가있다는점등이있어향후이에대한추가적인연구가필요할것으로판단된다. 위암수술환자에서영양상태를반영하는여러인자들과항암치료의순응도에관한상관관계를분석해보았을때치료시작전낮은혈청알부민수치를보인환자에서보조항암화학요법을중단하는경우가많다는것을본연구를통해확인할수있었다. 따라서혈청알부민농도는보조항암화학요법을시작하기전에치료의성공적인완료여부를예측하는인자로활용될수있을것이다. REFERENCES 1. Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN Int J Cancer 2015;136:E Park JY, von Karsa L, Herrero R. Prevention strategies for gastric cancer: a global perspective. Clin Endosc 2014;47: Elliott L, Molseed LL, McCallum PD. The clinical guide to oncology nutrition. 2nd ed. Chicago: American Dietetic Associati, Argilés JM. Cancer-associated malnutrition. Eur J Oncol Nurs 2005;9 Suppl 2:S Van Cutsem E, Arends J. The causes and consequences of cancer-associated malnutrition. Eur J Oncol Nurs 2005;9 Suppl 2:S Cessot A, Hebuterne X, Coriat R, Durand JP, Mir O, Mateus C, et al. Defining the clinical condition of cancer patients: it is time to switch from performance status to nutritional status. Support Care Cancer 2011;19: Seo SH, Kim SE, Kang YK, Ryoo BY, Ryu MH, Jeong JH, et al. Association of nutritional status-related indices and chemotherapy-induced adverse events in gastric cancer patients. BMC Cancer 2016;16: Washington K. 7th edition of the AJCC cancer staging manual: stomach. Ann Surg Oncol 2010;17: La Torre M, Ziparo V, Nigri G, Cavallini M, Balducci G, Ramacciato G. Malnutrition and pancreatic surgery: prevalence and outcomes. J Surg Oncol 2013;107: Sanford DE, Sanford AM, Fields RC, Hawkins WG, Strasberg SM, Linehan DC. Severe nutritional risk predicts decreased

5 40 Surgical Metabolism and Nutrition Vol. 8, No. 2, 2017 long-term survival in geriatric patients undergoing pancreaticoduodenectomy for benign disease. J Am Coll Surg 2014; 219: Katsube T, Konnno S, Murayama M, Kuhara K, Sagawa M, Yoshimatsu K, et al. Changes of nutritional status after distal gastrectomy in patients with gastric cancer. Hepatogastroenterology 2008;55: Kuzu MA, Terzioğlu H, Genç V, Erkek AB, Ozban M, Sonyürek P, et al. Preoperative nutritional risk assessment in predicting postoperative outcome in patients undergoing major surgery. World J Surg 2006;30: Pikul J, Sharpe MD, Lowndes R, Ghent CN. Degree of preoperative malnutrition is predictive of postoperative morbidity and mortality in liver transplant recipients. Transplantation 1994;57: Son MW, Lee MS. Association of preoperative nutritional factors with prognosis in gastric cancer patients. Surg Metab Nutr 2013;4: Hendifar A, Osipov A, Khanuja J, Nissen N, Naziri J, Yang W, et al. Influence of body mass index and albumin on perioperative morbidity and clinical outcomes in resected pancreatic adenocarcinoma. PLoS One 2016;11:e Lien YC, Hsieh CC, Wu YC, Hsu HS, Hsu WH, Wang LS, et al. Preoperative serum albumin level is a prognostic indicator for adenocarcinoma of the gastric cardia. J Gastrointest Surg 2004;8: Dionigi P, Nazari S, Bonoldi AP, Cividini F, Olezza S, Dionigi R. Nutritional assessment and surgical infections in patients with gastric cancer or peptic ulcer. JPEN J Parenter Enteral Nutr 1982;6: Fukuda T, Seto Y, Yamada K, Hiki N, Fukunaga T, Oyama S, et al. Can immune-enhancing nutrients reduce postoperative complications in patients undergoing esophageal surgery? Dis Esophagus 2008;21: Arrieta O, Michel Ortega RM, Villanueva-Rodríguez G, Serna- Thomé MG, Flores-Estrada D, Diaz-Romero C, et al. Association of nutritional status and serum albumin levels with development of toxicity in patients with advanced non-small cell lung cancer treated with paclitaxel-cisplatin chemotherapy: a prospective study. BMC Cancer 2010;10: Barret M, Malka D, Aparicio T, Dalban C, Locher C, Sabate JM, et al. Nutritional status affects treatment tolerability and survival in metastatic colorectal cancer patients: results of an AGEO prospective multicenter study. Oncology 2011;81:

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012임수진 Received : 2012. 11. 27 Reviewed : 2012. 12. 10 Accepted : 2012. 12. 12 A Clinical Study on Effect of Electro-acupuncture Treatment for Low Back Pain and Radicular Pain in Patients Diagnosed with Lumbar