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1 CASE REPORT Journal of Breast Cancer J Breast Cancer 2010 December; 13(4): DOI: /jbc 유방암에서발생한악성흉막삼출에대한흉강내 Paclitaxel 화학요법 박신영ㆍ최정은ㆍ전명훈ㆍ강수환ㆍ이수정 영남대학교의과대학외과학교실 Intrapleural Paclitaxel Chemotherapy in the Treatment of Breast Cancer-Related Metastatic Malignant Pleural Effusion Shin-Young Park, Jung-Eun Choi, Myung-Hoon Jeon, Su-Hwan Kang, Soo-Jung Lee Department of Surgery, Yeungnam University College of Medicine, Daegu, Korea Malignant pleural effusion in breast cancer has been associated with poor prognosis. The response rate of local treatment has been very low and in some case, complications have resulted in death. We investigated the efficacy and safety of paclitaxel, as an intrapleural chemotherapeutic agent. From January 2006 to December 2009, ten breast cancer patients who had developed malignant pleural effusion were infused with intrapleural paclitaxel through a chest tube, which was clamped for 48 hours. The chest tube was maintained until drainage was reduced to less than ml/day. The average time spent with a chest tube attached following intrapleural chemotherapy was 9.3 days. During the follow-up period, six patients had no recurrent pleural effusion and two received a second round of intrapleural chemotherapy following which no further pleural effusion recurred. There were no severe side effects except for mild toxicity. It is suggested that intrapleural paclitaxel chemotherapy may be superior to conventional local treatment and may represent an effective treatment modality with low toxicity. Key Words: Breast neoplasms, Malignant, Paclitaxel, Pleural effusion 중심단어 : 유방암, 악성, 파클리탁셀, 흉막삼출 서 악성종양환자에서악성흉막삼출은파종성혹은진행된병의상태를의미하며생존율을감소시킨다.(1) 악성흉막삼출의진단후생존기간은 3-12개월정도이며주로악성종양의병기에따라달라진다. 폐암에의한악성흉막삼출의생존율이가장짧은것으로보고되며난소암에의한경우가장긴생존율을보인다.(2) 악 책임저자 : 이수정 대구광역시남구대명5동 317-1, 영남대학교의과대학외과학교실 Tel: , Fax: crystallee@med.yu.ac.kr 접수일 : 2010년7월 9일게재승인일 : 2010년9월 30일본논문은 2010년 5월 28 일한국유방암학회춘계학술대회에서포스터로발표되었음. 론 성흉막삼출의가장흔한원인은남성에서는폐암이며여성에서는유방암으로, 전체악성흉막삼출의 50-65% 는이두가지암이차지한다.(3) 대부분의흉막삼출은전신적항암요법에반응률이낮으며고식적인방법이치료의대부분을차지한다. 악성흉막삼출의국소치료로는흉관삽입술과흉강내로의경화제투여법이이용되었으며과거에는 tetracycline을이용한흉막유착술이흔히시행되었고그외에 doxycycline, nitrogen mustard, bleomycin 및탈크 (talc) 등이이용되었다.(4) 이러한치료법중탈크를이용한흉막유착술이현재선택적인치료법으로 90% 의높은반응률을보이나문헌에의하면탈크로인한성인호흡곤란증후군이 21 예에서보고되는등치명적인합병증을유발하며드물지만사망에이르기도한다.(5) Paclitaxel은유방암의치료에이용되고있는효과적인항암 443

444 Shin-Young Park, et al. 제로불수용성이며분자량이비교적큰특징을지니고있다. 이러한특징으로흉강내에잔류되는기간이길어짐으로써암세포에노출되는시간이수용성약제에비해길어지며전신적독성은감소되는효과를가진다.

환자는입원하여화학요법제투여전기본적인영상의학검사로 chest PA, lateral decubitus view를촬영한후 (Figure 1), 흉관을삽관하고 paclitaxel 투여전까지삼출액을충분히배액시켰다.

Paclitaxel 투여후흉관을차단하여약제를흉강내에저류시킨후 48 시간후배액하여 1일배액 량이 50-100 ml 이하로되면흉관을제거하고추적조사하였다.

2 444 Shin-Young Park, et al. 제로불수용성이며분자량이비교적큰특징을지니고있다. 이러한특징으로흉강내에잔류되는기간이길어짐으로써암세포에노출되는시간이수용성약제에비해길어지며전신적독성은감소되는효과를가진다.(6) 이러한약제의특성을이용하여저자들은유방암에서발생한악성흉막삼출에대하여흉강내 paclitaxel 화학요법을시행하였으며그에따른악성흉막삼출액의조절효과와안전성에대하여분석하였다. 증례본원에서유방암으로치료받은환자중 2006년 1월부터 2009년 12 월까지악성흉막삼출로진단되어흉강내 paclitaxel 화학치료를시행받은 10 명의여자환자를대상으로후향적으로분석하였다. 환자는입원하여화학요법제투여전기본적인영상의학검사로 chest PA, lateral decubitus view를촬영한후 (Figure 1), 흉관을삽관하고 paclitaxel 투여전까지삼출액을충분히배액시켰다. 삼출액을배액시킨후 chest PA를재촬영하여삼출액이충분히배액되고폐가완전히팽창된것을확인한후 paclitaxel (Padexol, Shinpoong Pharm., Seoul, Korea) 120 mg/m 2 을생리식염수 200 ml에혼합하여흉관을통해투여하였다. 환자들은전신적항암화학요법에서처럼 paclitaxel 투여전수액요법과항구토제를투여받았다. Paclitaxel 투여후흉관을차단하여약제를흉강내에저류시킨후 48 시간후배액하여 1일배액 량이 ml 이하로되면흉관을제거하고추적조사하였다. 독성과치료반응평가는약제투여후증상, 이학적검사, 활력상태및혈액학적지표로확인하였으며 10 명의환자모두악성흉막삼출의치료에대해 1차적으로흉강내화학요법치료후전신적항암화학요법을시행하였으며퇴원후 chest PA, chest CT 및 PET-CT 등의영상학적검사로매 6개월마다평가하였다 (Figure 2). 대상환자 10명의평균연령은 42.4세 (33-48세) 였으며평균추적기간은 10.3개월 (3-30개월 ) 이었다. 대상환자 10명중 1명은유방암원발병변에대한수술을시행하지않았으며임상적병기 Figure 2. Three months after intrapleural chemotherapy. Significant decrease of pleural effusion was seen and right lung reexpanded fully. Figure 1. Chest CT scan performed on admission. Chest CT scan obtained in a 43-yr-old woman who presented with dyspnea shows a large amount of right pleural effusion with total collapse of the right lung.

3 Intrapleural Paclitaxel Chemotherapy 445 는 stage IIIc였고수술을시행한 9명의환자의조직학적병기는 stage I이 1명, stage II가 3명, stage III가 3명이었다 (Table 1). 10 명의환자모두다발성원격전이가발생한환자였으며 7명은악성흉막삼출이진단되기전에다발성원격전이가있었던환자였으며 3명은악성흉막삼출진단당시원격전이가처음발견된환자였다. 흉강내화학요법치료후흉막삼출의양이감소하여흉관을제거하는데까지걸린시간은평균 9.3 일이었다 (2-20일). 흉강내 paclitaxel 화학요법시행후 6명의환자는추적기간내에흉막삼출의재발이없었으며 4명의환자에서흉막삼출이재발되었다 (Table 2). 재발된 4명의환자중 2명의환자는 1차흉강내화학요법후각각 4개월, 6개월뒤에재발하여 2차흉강내화학요법을시행하였으며남은추적기간동안재발은없었다. 재발된 4명의환자중다른 2명의환자는치료후각각 3개월, 5개월에재발되었으나삼출액의양이적고흉막삼출로인한증상이없어흉막삼출에대한추가적인국소치료를시행하지않았다. Table 1. Patient characteristics: primary breast cancer Case no. Sex/Age Surgical procedure Stage Hormone receptor (ER/PR/erb-B2) Adjuvant systemic chemotherapy Hormone therapy 1 F/47 MRM w/ ALND IIIA -/+/+ Epirubicin-Navelbine Moxafen CMF, Furtulon 2 F/33 NASSM w/ ALND IIIC +/+/- FEC Tamoxifen -Epirubicin 3 F/46 MRM w/ ALND IIIC +/-/1+ AC Tamoxifen 4 F/43 BCS w/ ALND IIIC +/+/1+ FAC Tamoxifen 5 F/48 MRM w/ ALND IIA +/+/- AC Tamoxifen 6 F/46 MRM w/ ALND IIB -/-/- FAC - Padexol 7 F/47 BCS w/ ALND IIB -/-/- AC - 8 F/42 BCS w/ SLND I -/-/3+ FEC - 9 F/34 - IIIC +/-/3+ Taxotere-Adriamycin - 10 F/38 MRM w/ ALND IIIC +/+/- AC Tamoxifen ER=estrogen receptor; PR=progesterone receptor; MRM=modified radical mastectomy; CMF=Cyclophosphamide+methotrexate+5-fluorouracile; NASSM=nipple-areola preserving skin-sparing mastectomy; ALND=axillary lymph node dissection; FEC=5-fluorouracile+epirubicin+cyclophosphamide; BCS=breast conserving surgery; AC=adriamycin+cyclophosphamide; SLND=sentinel lymph node dissection; FAC=5-fluorouracile+ adriamycin+cyclophosphamide. Table 2. Patient characteristics: metastatic malignant pleural effusion Case no. Effusion after diagnosis of breast cancer (mo) Diagnosis methods Chest tube indwelling period after chemotherapy (days) Systemic chemotherapy after IP chemotherapy Pleural recur Cytology 3 Xeloda Yes, 4 mo later 2 71 Cytology 2 Taxotere-Xeloda Yes, 6 mo later 3 61 PET-CT 10 Padexol-Cisplatin No 4 59 Cytology 11 Taxotere-Xeloda No 5 50 Cytology 3 FEC No 6 19 PET-CT 20 Taxotere-Xeloda No 7 28 Cytology 18 Padexol-Cisplatin Yes, 3 mo later 8 23 PET-CT 10 Padexol-Herceptin Yes, 5 mo later 9 9 PET-CT 6 Padexol-Herceptin No Cytology 10 Gemcit-Cisplatin No IP=intrapleural; PET-CT=positron emission tomography-computed tomography; FEC=5-fluorouracile+epirubicin+cyclophosphamide.

4 446 Shin-Young Park, et al. Table 3. Complication of intrapleural chemotherapy Case no. Complication Days after intrapleural chemotherapy 흉강내 paclitaxel 화학요법후치명적인부작용은발생하지않았으며 6명의환자에서호중성백혈구감소증이발생하였으며 grade I이 3명, grade II가 3명이었다. 경미한흉통과폐렴이각각 1명의환자에서발생하였다 (Table 3). 대상환자 10 명중 2명은추적기간중사망하였고현재 8명은전신적항암화학요법을시행하면서정기추적관찰중이다. 사망한 2명의환자모두악성흉막삼출진단당시다발성전이가있었던환자였으며 2명중 1명은흉강내화학요법두차례시행후악성흉막삼출의재발은없었으나다발성간전이, 뼈전이, 림프절전이가진행되어사망하였고다른 1명은다발성뼈전이및복강내전이로치료중연수막전이로사망하였으며경미한흉막삼출이동반되어있었다. 고 악성흉막삼출은진행성악성종양에서사망률을증가시키는주된원인이되며,(7) 주된생성기전은벽측흉막의침범으로인한림프액배출저해, 종격동내임파절의팽대에의한역류등이다.(8) 대부분의환자들은삶의질을방해할정도의심한호흡곤란을경험한다.(9,10) 반복적인흉강천자를시행하는경우일시적인증상의완화를가져올수있으나대부분수일이내에재발하며,(11) 흉막제거술은효과적이기는하지만유병률과사망률이높은것으로알려져있다.(12) 고식적치료의하나로흉관삽관후흉강내경화제투여가많이이용되어왔으며사용되는경화제로는 tetracycline, 찰 Treatment 1 Neutropenia (grade I) 7 Thymomodulin Pneumonia 2 Filgrastim Antibiotics 2 Neutropenia (grade II) 5 Thymomodulin Chest pain 1 Filgrastim Analgesic (codeine) NSAID (ketorolac tromethamine) 3 Neutropenia (grade I) 7 Thymomodulin 5 Neutropenia (grade I) 4 Thymomodulin 8 Neutropenia (grade II) 12 Thymomodulin Filgrastim 9 Neutropenia (grade II) 6 Thymomodulin Filgrastim NSAID=nonsteroidal antiinflammatory drug. doxycycline, bleomycin 등이있다. 보고에의하면탈크를이용한치료법이가장높은성공률을보이고있으나호흡곤란을악화시키며호흡곤란증후군을일으키기도한다.(13) 하지만흉강내화학요법은기존의경화요법과비교하여흉막삼출액의조절뿐만아니라전신부작용을최소화하면서악성세포에대한직접적인치료효과를나타낼수있다는점에서악성흉막삼출에대한새로운치료법으로선택할수있는방법이다. 보고된약동학연구에의하면흉강내에서 paclitaxel의청소율은극도로낮아 225 mg/m 2 의 paclitaxel을흉강내에주입한후 24 시간이경과하였을때흉강내 paclitaxel의 50% 정도만유지되는것으로알려졌다.(14) 이연구에서 paclitaxel의최고혈중농도 (Cmax, peak plasma concentration) 는약 0.35 μmol/l 였으며이는흉강내농도 (24시간내흉강내 paclitaxel 농도, μmol/l) 보다훨씬낮은수치이다. 이러한특성으로 paclitaxel은흉강내에서악성세포가약제에노출되는시간을연장시킬수있으며약제에의한전신적독성은감소시킬수있다. 하지만이러한약동학적장점에비해 paclitaxel을유방암환자에서흉강내치료로이용한연구는거의없는실정이다. 최근 Ohta 등 (6) 은 12 명의폐암환자와 1명의유방암환자에서발생한악성흉막삼출을 24 시간흉강내 paclitaxel 주입법으로치료한결과를발표하였다. 이연구에서평균 9개월의추적기간동안 11 명 (84.6%) 의환자에서흉막삼출이성공적으로조절되었다. 치료의부작용으로는 4명에서중성백혈구감소증, 흉통등이발생하였고 5명의환자는항암요법에대한독성이나타나지않았다. 본연구에서도대상환자 10명중 8명에서 1차또는 2차흉강내 paclitaxel 주입법으로흉막삼출이성공적으로조절되었으며치료가필요한흉막삼출의재발은 2명이었고치명적인부작용이나타난환자는한명도없었다. 결론적으로 paclitaxel을이용한흉강내화학요법은흉막삼출이소실되기까지걸리는시간을앞당김으로써흉관의거치시간을줄일수있다는점에서기존의국소치료법보다우수한치료법으로생각한다. 또한전신적독성이적으면서도흉막삼출액의조절뿐만아니라흉강내에있는전이성악성세포에대한직접적인세포독성효과가있다는점에서흉강내 paclitaxel 화학요법은유방암환자에서발생한악성흉막삼출의치료로고려해볼만한치료법이라고생각한다. 참고문헌 1. Barbetakis N, Antoniadis T, Tsilikas C. Results of chemical pleurodesis with mitoxantrone in malignant pleural effusion from breast cancer. World J Surg Oncol 2004;2:16.

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( )Jkstro011.hwp 비인강암의방사선치료결과및생존율에관한예후인자분석 2005 2 1 2005 3 28. :, Tel: 053)250-7665, Fax: 053)250-7984 E-mail: jhkim@dsmc.or.kr 정영연외 2 인 : 비인강암의예후인자분석 정영연외 2 인 : 비인강암의예후인자분석 Carcinoma of the nasopharynx treated by radiotherapy