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1 Practice Guideline For Ovarian Cancer 제작및발행 : 부인종양학회 Korean Society of Gynecologic Oncology 후원 :

2 목 차 V3.0 의개정사항요약 1 I. 서론 4 II. 상피성난소암 8 1. 진단검사 8 2. 일차치료 8 3. 보조항암화학요법 일차보조항암화학요법후의추가치료 추적관찰 재발성난소암의치료 12 III. 경계성상피성난소종양 진단및치료 관찰및재발암의치료 14 IV. 기타난소암 진단및치료 관찰및재발암의치료 15 V. 요약 17 VI. 참고문헌 23 [ 부록 1] V3.0 의핵심질문및 PICO 25 [ 부록 2] V3.0 의핵심질문및개별참고문헌 27 [ 부록 3] V2.0 의핵심질문 59

3 V3.0 의개정사항요약 V3.0 의핵심질문 KQ 1 KQ 2 KQ 3 KQ 4 KQ 5 KQ 6 KQ 7 KQ 8 질문 임상적으로난소에국한된조기상피성난소암환자에서체계적골반그리고 / 또는대동맥주 위림프절절제술은생존율을향상시키는가? 임상적으로난소에국한된조기상피성난소암환자에서체계적골반그리고 / 또는대동맥주 권고사항 위림프절절제술시행은미시행또는선택적절제술에비해생존율을유의하게향상시킨 다는근거가부족하나, 임상적판단하에시행할수있다. 권고수준 Level 2B 질문 최적종양감축이어려울것으로판단되는진행성상피성난소암에서선행화학요법후종양감축술이일차종양감축술에비해생존율에차이가없는가? 권고사항 최적종양감축이어려울것으로판단되는진행성상피성난소암에서선행화학요법후종양감축술이일차종양감축술과비교하여생존율에차이가없으므로, 시행할수있다. 권고수준 Level 2A 질문 진행성상피성난소암에서수술후일차용량집중항암화학요법은생존율을향상시키는가? 권고사항 권고수준 질문 [4.1] 권고사항권고수준 진행성상피성난소암에서수술후일차용량집중항암화학요법은기존의표준항암화학요법에비해독성이높으나생존율을유의하게향상시킬수있으므로, 임상적판단하에시행할수있다. Level 2B 상피성난소암환자에서수술후일차및재발시이차치료로서 bevacizumab이생존율을향상시키는가? 상피성난소암환자에서수술후일차요법으로서 bevacizumab은무진행생존율을향상시키므로, 사용할수있다. Level 2A 백금민감성재발성상피성난소암환자에서이차요법으로서 bevacizumab은무진행생존율을향상시키므로, 사용할수있다. 단, 백금저항성재발성상피성난소암환자에서이차요법으 [4.2] 권고사항 로서 bevacizumab 은우선적으로권고된다. 권고수준 Level 2A ( 백금저항성은 level 1) 자궁부속기종양이있는환자에서 ROMA 는난소암감별진단의민감도와특이도에있어서 질문 CA-125보다우수한가? 권고사항 자궁부속기종양이있는환자에서난소암감별진단을위해 ROMA를시행할수있다. 권고수준 Level 2D 질문 장액성경계성난소종양에서포괄적병기설정술이생존율을향상시키는가? 권고사항 장액성경계성난소종양에서포괄적병기설정술이생존율을향상시킬수있는지에대한근거수준은현재평가하기어려워, 시행권고수준결정을유보하기로하였다. 권고수준 Level E 질문 향후임신을원하는젊은조기상피성난소암환자에서임신능력보존수술은생존율에영향을미치는가? 권고사항 향후임신을원하는젊은, 조기상피성난소암환자에서포괄적병기설정술을시행할때, 임신능력보존수술은생존율을떨어뜨리지않으므로, 시행할수있다. 권고수준 Level 2D 질문 BRCA-관련난소암에서 PARP 억제제유지요법은생존율을향상시키는가? 권고사항 BRCA-관련난소암에서, 특히 BRCA 돌연변이가있는백금민감성재발성난소암환자에서, PARP 억제제유지요법은무진행생존율을향상시키므로, 사용한다. 권고수준 Level 1D 1

4 부인암진료권고안 v.3.0 V3.0 본문의추가및변경사항 상피성난소암 진단검사 난소암이의심되는골반종양 [ 추가 ] 자궁부속기종양이있는환자에서난소암감별진단을위해 ROMA 를시행할수있다. ( 권고수준 2D) ( 근거표 5) 일차치료 ; 난소암이의심되는골반종양 조기상피성난소암환자의일차수술치료 [ 권고등급 / 근거수준변경 ] 임상적으로난소에국한된조기상피성난소암환자에서골반그리고 / 또는대동맥주위림프절절제술 (systemic pelvic and/or paraaortic lymphadenectomy) 은미시행또는선택적절제술에비해생존율을유의하게향상시킨다는근거가부족하나, 임상적판단하에시행할수있다. ( 권고수준 1D) ( 권고수준 2B) ( 근거표 1) [ 추가 ] 향후임신을원하는젊은조기상피성난소암환자에서포괄적병기설정술을시행할때, 임신능력보존수술 (fertility-sparing surgery) 은생존율을떨어뜨리지않으므로, 시행할수있다. ( 권고수준 2D) ( 근거표 7) 진행성상피성난소암환자의일차수술치료 [ 권고등급 / 근거수준변경 ] 최적종양감축 (Optimal cytoreduction) 이어려울것으로판단되는진행성상피성난소암에서선행화학요법후종양감축술 (interval cytoreductive surgery) 을시행할수있다. ( 권고수준 E) ( 권고수준 2A) ( 근거표 2) 보조 (adjuvant) 항암화학요법, 일차보조항암화학요법후의추가치료, 재발성난소암의치료 용량집중항암화학요법 (dose-dense chemotherapy) [ 근거추가 ] 진행성상피성난소암에서수술후일차용량집중항암화학요법은기존의표준항암화학요법에비해독성이높으나생존율을유의하게향상시킬수있으므로, 임상적판단하에시행할수있다. ( 권고수준 2B 유지 ) ( 근거표 3) 표적치료 [ 추가 ] 상피성난소암환자에서수술후일차 (first-line) 및재발시이차 (second-line) 치료로서 bevacizumab 은무진행생존율을향상시키므로사용할수있다. ( 일차요법 : 권고수준 2A; 이차요법백금민감성재발 : 권고수준 2A; 이차요법백금저항성재발 : 권고등급 1) ( 근거표 4) [ 추가 ] BRCA- 관련난소암에서, 특히 BRCA 태생적돌연변이 (germline mutation) 가있는백금민감성재발성난소암환자에서, PARP(poly[ADP-ribose] polymerase) 억제제유지요법은무진행생존율을향상시키므로, 사용한다. ( 권고수준 1D) ( 근거표 8) 경계성상피성난소종양 진단및치료 [ 추가 ] 장액성경계성난소종양 (serous borderline ovarian tumor) 에서포괄적병기설정술 (comprehensive staging operation) 이생존율을향상시킬수있는지에대한근거수준은현재평가하기어려워, 시행권고수준결정을유보하기로하였다. ( 권고수준 E) ( 근거표 6) 2

5 [ 내용수정 ] 수술결과침윤성착상병변이있는경우관찰하거나, 상피성난소암과같이보조항암화학요법을시행하거나임상시험을권장할수있다. 수술결과침윤성착상병변이있는경우관찰하거나, 상피성난소암과같이보조항암화학요법을시행할수있다. 3

6 부인암진료권고안 I. 서론 난소암은가장치명적인부인암으로서선별검사와증상을바탕으로한조기발견이효과적으로사망률을낮추지못하는것으로알려져있다. 난소암은그종류가다양하여, 85% 이상을차지하는상피성난소암과그외생식세포종양그리고성삭간질종양으로분류된다. 상피성난소암은최근발암의기원, 분자생물학적발생기전, 임상양상등을바탕으로 1형과 2형으로분류되고있다. 1형은 2형보다드물게발생하고, 조기에발견되는경향이있으며대개전구병변으로부터발생한다. 2형은진행성병기에서많이발견되며난소암사망의대부분을차지하기때문에, 치료와예방의초점이주로 2형난소암에집중되어있다. 이런 2형난소암은최근나팔관의상피세포에서기원한다는가설이거의정설로받아들여지고있고, 1 이를바탕으로대규모연구들이양성질환으로수술시양측난관절제술 (bilateral salpingectomy) 을함께시행했을때효과적으로난소암발생을예방할수있다는결과들을보고하였다. 2,3 난소암발생은 25세이하의젊은연령에임신과출산을하였을경우, 경구피임약을복용한경우, 수유를한경우에 30-60% 감소된다고알려져있다. 이와반대로미산부이거나첫출산이 35세이상으로높을경우에는위험이증가된다고알려져있다. BRCA1과 BRCA2 유전자의변이 (germline mutation) 또는유전성비용종성대장직장암 (HNPCC) 을포함한가족력이있는경우난소암발생의위험이증가된다고알려져있고, 이러한유전성난소암은전체난소암환자의약 10% 정도를차지한다. BRCA1 또는 BRCA2 유전자변이가있는고위험군환자에서예방적난소난관절제술은난소암및나팔관암의발병을약 80% 줄일수있지만, 일차성복막암의위험도는여전히존재한다. 2015년 1월갱신된보건복지부암등록통계에따르면, 난소암은최근 5년간서서히증가하는양상으로, 연발생자수 ( 명 )/ 조발생율 ( 명 /10만명 ) 이 2008년 1,870/7.6, 2009년 1,832/7.4, 2010년 2,025/8.1, 2011년 2,025/8.1, 2012년 2,167/8.6으로나타났다. 2012년여성암발생의 1.9% 로 10위를차지하였다. 연령대별로는 50대가 28.6% 로가장많았으며, 이어 40대가 21.0%, 60대가 17.2% 를차지하였다. 발생율이크게증가하지는않았지만, 5년생존율은 년 58.7% 에서 년 61.9% 로거의향상되지않고제자리걸음을하고있어, 유방암 (78.0% 에서 91.3% 로증가 ), 대장암 (54.2% 에서 71.8% 로증가 ), 위암 (42.6% 에서 70.0% 로증가 ), 폐암 (14.2% 에서 28.2% 로증가 ) 등주요암종의치료성적향상에비추어볼때, 획기적인난소암치료법의개발이시급한상황임을알수있다. 4

7 본은 2013 세계보건기구난소종양조직학적분류 (WHO classification of ovarian neoplasms) (Table 1) 와 2014년도새롭게개정된 FIGO 병기 (2014 New FIGO Ovarian Cancer Staging) 를이용하였다 (Table 2). 본진료권고안은 부인암진료권고안 V2.0, 2010 을근간으로최근의변화된내용을추가하는방식으로작성되었으며, 진료현장에서궁금해하는핵심질문 들을전문가들의회의를거쳐도출하여, 부록형식으로근거표와근거 / 권고수준을함께표기하여 수록하였다. Table 1. Modified WHO classification of tumors of the ovary A. Epithelial tumors Serous tumors ㆍ Borderline - Serous borderline tumor - Serous borderline tumor, micropapillary variant/non-invasive low-grade serous carcinoma ㆍ Malignant - Low-grade serous carcinoma - High-grade serous carcinoma Mucinous tumors ㆍ Borderline ㆍ Malignant Endometrioid tumors ㆍ Borderline ㆍ Malignant Clear cell tumors ㆍ Borderline ㆍ Malignant Brenner tumors ㆍ Borderline ㆍ Malignant Seromucinous tumors ㆍ Borderline ㆍ Malignant Undifferentiated carcinoma B. Mesenchymal tumors Low-grade endometrioid stromal sarcoma High-grade endometrioid stromal sarcoma C. Mixed epithelial and mesenchymal tumors Adenosarcoma Carcinosarcoma D. Sex cord-stromal tumors Granulosa cell tumor ㆍ Adult ㆍ Juvenile Sertoli-Leydig cell tumor Fibrosarcoma E. Germ cell tumors 5

8 부인암진료권고안 v.3.0 Dysgerminoma Yolk sac tumor Embryonal carcinoma Non-gestational choriocarcinoma Immature teratoma F. Somatic-type tumors arising from a dermoid cyst Struma ovarii, malignant Carcinoid: Strumal carcinoid/mucinous carcinoid Sebaceous carcinoma Squamous cell carcinoma G. Miscellaneous tumors Small cell carcinoma, hypercalcemic type Small cell carcinoma, pulmonary type H. Lymphoid and myeloid tumors I. Secondary tumors Table 2. FIGO and TNM surgical staging system for ovarian cancer FIGO FIGO FIGO I T1 Tumor confined to ovaries IA IB IC T1a T1b Tumor limited to 1 ovary (capsule intact); no tumor on ovarian surface; no malignant cells in the ascites or peritoneal washings Tumor limited to both ovaries (capsules intact); no tumor on ovarian surface; no malignant cells in the ascites or peritoneal washings Tumor limited to 1 or both ovaries, with any of the following IC1 T1c1 Surgical spill IC2 T1c2 Capsule ruptured before surgery or tumor on ovarian surface IC3 T1c3 Malignant cells in the ascites or peritoneal washings II T2 Tumor involves 1 or both ovaries with pelvic extension (below pelvic brim) or primary peritoneal cancer IIA T2a Extension and/or implants on uterus and/or fallopian tubes IIB T2b Extension to other pelvic intraperitoneal tissues III Tumor involves 1 or both ovaries, with cytologically or histologically confirmed spread to the peritoneum outside the pelvis and/or metastasis to the retroperitoneal lymph nodes 6

9 IIIA1 T1/T2-N1 Positive retroperitoneal lymph nodes only (cytologically or histologically proven): IIIA1(i) IIIA1(ii) IIIA2 IIIB IIIC T3a2-N0/N1 T3b-N0/N1 T3c-N0/N1 Metastasis up to 10 mm in greatest dimension Metastasis more than 10 mm in greatest dimension Microscopic extrapelvic (above the pelvic brim) peritoneal involvement with or without positive retroperitoneal lymph nodes Macroscopic peritoneal metastasis beyond the pelvis up to 2 cm in greatest dimension, with or without metastasis to the retroperitoneal lymph nodes Macroscopic peritoneal metastasis beyond the pelvis more than 2 cm in greatest dimension, with or without metastasis to the retroperitoneal lymph nodes (includes extension of tumor to capsule of liver and spleen without parenchymal involvement of either organ) IV IVA IVB Any T, Distant metastasis excluding peritoneal metastasesany N, M1 Pleural effusion with positive cytology Parenchymal metastases and metastases to extra-abdominal organs (including inguinal lymph nodes and lymph nodes outside of the abdominal cavity) 7

10 부인암진료권고안 v.3.0 II. 상피성난소암 1. 진단검사 (1) 난소암이의심되는골반종양난소암이의심되며, 난소이외다른부위의암이의심되지않는골반종양 ( 또는복수 ), 복부팽만등의증상이있는환자의일차적인진단검사로는문진, 진찰과종양표지자검사를시행한다. 일차적으로혈청 CA-125 측정이권장되며, 임상적상황에따라 CA 19-9 혹은 CEA 등의측정을시행할수있고, 만일생식세포종양이의심된다면 AFP 및 β-hcg 측정을시행할수있다. 비교적최근개발되어사용되고있는 Human epidydimis protein-4 (HE-4) 는난소암감별진단에있어서 CA-125와함께사용함으로써 (ROMA, risk of ovarian malignancy algorithm), CA-125 단독사용보다민감도와특이도에있어서더우수하다는보고가있으나, 아직근거수준이낮은상태로임상적판단하에사용할수있다 ( 권고수준 2D, 근거표 5). 또한기본검사 ( 일반혈액검사, 일반생화학검사, 흉부 X-선검사, 심전도검사와요검사 ) 및영상진단 ( 임상적필요성에따라골반초음파검사, 복부 -골반 CT/MRI/PET, 흉부 CT) 을시행한다. 난소암 ( 또는유방암 ) 의가족력이있는환자는유전상담도고려해야한다. 다른부위로부터난소로의전이를배제하기위하여위장관검사를시행한다. (2) 수술후난소암으로진단된경우수술후병리조직학적으로난소암진단이이루어진후전원되는경우가있는데, 이들중일부는이미종양감축술 (cytoreductive surgery) 과포괄적병기설정술 (comprehensive surgical staging) 이시행된경우도있다. 그러나불완전한수술또는불충분한병기설정술 ( 자궁또는자궁부속기미절제, 대망미절제, 절제가능한잔류병변이있는경우, 수술적병기결정에대한완전한의무기록이없는경우등 ) 후에전원되는경우도있다. 이러한환자에서의진단검사는전술한바와같은절차를시행한다. 또한모든환자에서기존병리조직의재검토가추천된다. 2. 일차치료 (1) 난소암이의심되는골반종양적절한일차치료는수술적병기결정및 / 혹은종양감축술과수술후보조항암화학요법으로구성된다. 난소암이의심되어병기설정술, 일차종양감축술, 선행항암화학요법이후종양감축술 (interval cytoreductive surgery) 을시행하거나, 또는재발후이차종양감축술 (secondary cytoreductive surgery) 시행예정인환자에서수술적치료는복벽정중절개를통한개복수술로시행되어야한다. 하지만, 새롭게진단된환자에서명백하게난소또는골반내국한된경우선택적으로복강경수술을포함한최소침습수술 (minimally invasive surgery) 이고려될수있다. 최소침습수술은숙련된부인종양전문의에의해조기병기환자에서선택적으로시행을고려할수있다 ( 권고수준 2D). 하지만, 최소침습수술로써적절한최대종양감축을시행할수없다고판단될경우반드시개복술로의전환이필요하다. 최소침습수술은새롭게진단된또는재발성난소암에서최대종양감축이가능할지여부를판단하기위한목적으로도유용하게사용될수있다. 복강내진입즉시복수가있다면복수가없어도골반및복부세척세포검사를시행하여야한다. 수술중동결절편검사는치료방침결정에도움을줄수있다. 모든복막표면을확인하여전이가의심되는모든복막과유착부위를제거하거나생검하여야한다. 의심되는부위가없을때에는골반, paracolic gutters, 횡경막아래표면에서무작위로복막생검을해야한다. 횡경막표면복막생검대신자궁 8

11 경부세포검사에서처럼표면을긁어세포검사를할수도있다. 완전한병기설정술은골반및복부세척세포검사이외에전자궁절제술, 양측난관-난소절제술, 대망절제술, 골반 / 대동맥주위림프절절제술, 다수의복막생검과전이가있거나의심되는부위에대한최대종양감축을포함한다. 전자궁절제술과양측난관-난소절제술을시행하면서종양은피막이터지지않고온전하게제거될수있도록최대한노력해야한다. 이때, 임신을원하는환자의경우조직분화도와관계없이수술소견상병기 IA 혹은 IC를보이면포괄적병기설정술 (comprehensive surgical staging) 을시행할때, 자궁과한쪽자궁부속기를보존하는임신능력보존수술 (fertility-sparing surgery) 을시행할수있다 ( 근거수준 2D, 근거표 7). 임신능력보존포괄적병기설정술이란임신능력의보존을위하여집도의의판단에따라자궁및일측난소 ( 난관 ) 를보존하면서, 복강및후복강의모든장기에대한철저한육안적검사와광범위한조직검사를통하여완전한병기결정수술을대체하는것으로정의한다. 대동맥주위림프절절제는대정맥과대동맥부터양측으로적어도아래창자간막동맥 (inferior mesenteric artery) 까지, 선호되기로는신동정맥수준까지시행되어야한다. 골반림프절절제시선호되는방법은총장골혈관 (common iliac vessel) 상부와내측 (medial), 외장골혈관 (external iliac vessel) 상부와내측, 내장골혈관 (hypogastric vessels) 상부와내측, 그리고최소한폐쇄오목 (obturator fossa) 에서부터폐쇄신경 (obturator nerve) 앞쪽까지시행되어야한다. 골반그리고 / 또는대동맥주위림프절절제술은임상적으로난소에국한된조기상피성난소암에서도미시행또는선택적절제술에비해생존율을향상시킨다는근거는부족하나, 임상적판단하에시행할수있다 ( 권고수준 2B, 근거표 1). 병기 II, III, IV기환자의경우일차적으로최대종양감축술이추천된다. 일반적으로잔류종양이 1cm 미만일때적절한종양감축이이루어진것으로간주하지만, 잔류종양이하나도없을때가장우수한생존율을보이기때문에수술의사는눈에보이는모든종양을제거하여육안적으로보이는잔류종양을남기지않도록최대한노력해야한다. 4 그러나, 일차수술로최적종양감축이어려울것으로판단되는병기 III-IV 환자는수술전에선행항암화학요법을시행하고이후추가적종양감축술을고려할수있다 ( 권고수준 2A, 근거표 2). 그러나이러한경우에는선행항암요법전반드시종양에대한세침흡인술, 생검혹은복수천자로써난소암의세포 / 병리조직학적진단이선행되어야한다. 진행된난소암에서선행항암화학요법후수술을시행하는것이일차수술후보조항암화학요법과비교하여생존율에차이가없으면서, 수술에따른합병증이감소하는장점을보였다. 5,6 잔류종양이 1cm 미만으로남은경우선행항암화학요법후수술시행과일차수술후보조항암화학요법을시행하는것과생존율의차이가없었다. 하지만, 치료전전이종양의크기가 5cm 미만인경우일차수술후보조항암화학요법을시행하는것이전체생존율이더우수하기때문에 ( 위험도 0.64; 95% 신뢰구간 ), 5cm 이상의전이성종양을포함하는복막파종이있어최적종양감축을기대하기어려운경우선행항암화학요법을시행할수있다. 골반과상복부를함께침범한난소암에서도골반및복부세척세포검사, 종양침범이의심되는대망과림프절은모두제거되어야하며, 적절한종양감축의달성을위하여장절제, 충수돌기절제 ( 점액성난소암의경우 ), 횡경막과그외다른복막표면의종양절제 (stripping 또는 peritonectomy), 비장절제, 방광의부분절제, ureteroneocystotomy, 간부분절제, 위부분절제, 담당절제, 원위부췌장절제등의다장기절제 (multi-visceral resection) 가고려될수있다. 이런수술적치료후 1cm 미만의잔류종양만이남은일부환자들에서수술후복강내항암치료를시행할수있다. 복강내항암치료를계획한다면, 일차수술치료시에복강내항암치료시행을위한카테터를유치해야한다. 완전한병기설정술은부인종양전문의에의해시행되어야하며, 본진료권고안에서도이를추천한다. 9

12 부인암진료권고안 v.3.0 (2) 수술후난소암으로진단된경우불완전한병기결정이이루어진환자혹은불완전한수술이시행된경우다음의원칙에따라치료를시행한다. 첫째, 병기 IA 또는 IB, 조직분화도 1로추정되는경우완전한병기설정술을시행한다. 만약추정되는병기가맞다면, 추가치료가필요없기때문이다. 둘째, 절제가능한잔류종양이남아있는것으로의심된다면, 종양감축술을포함한병기설정술을시행하는것이권고된다. 셋째, 병기가 IA 또는 IB, 조직분화도 1보다진행되고, 잔류종양이없다고생각되면, 항암치료또는완전병기설정술을고려할수있다. 병기 IA 또는 IB, 조직분화도 2인경우는항암치료없이관찰도가능하다. 넷째, 병기 II-IV인경우에잔류종양이없다고판단되면항암화학요법을 6-8회시행하거나, 수술에의한적절한절제가불가능한잔류종양이의심되는경우는항암화학요법을 3-6회시행후절제가능하다고생각될때종양감축술을시행하고, 수술후항암화학요법을추가할수있다. 3. 보조 (adjuvant) 항암화학요법대부분의상피성난소암환자는수술후보조항암화학요법을받게된다. 그러나병기 IA 혹은 IB이면서조직분화도 1인경우에는수술만으로 90% 이상의생존율을보이므로보조항암화학요법없이경과관찰한다. 병기 IA 혹은 IB이면서조직분화도 2인경우에는추가치료없이추적관찰을시행하거나 taxane/platinum 항암화학요법을 3-6회투여한다. 그러나병기 IA 혹은 IB이면서분화도가 3인경우 ( 투명세포암모두포함 ) 와모든 IC의경우에는분화도와상관없이 taxane/platinum 항암화학요법을 3-6회투여하여야한다. 병기 II-IV인경우에는수술후 taxane/carboplatin을 6-8회투여하는것이원칙이다. 일차수술이부적절하게이루어진경우 ( 선행항암화학요법을시행한경우도포함 ) 에는 3-6회항암화학요법후절제가능성과종양의약제반응성에따라선별적으로추가종양감축술 (interval cytoreductive surgery) 을시행할수도있다. 수술후최대직경 1cm 미만의잔류종양이남은병기 III기와병기 IV의경우에는복강내항암화학요법 (intraperitoneal chemotherapy) 이우선추천될수있다. ( 권고수준 2A) 진행성난소암에서 paclitaxel/carboplatin 매주사용용량집중 (dose-dense) 요법은호중구감소증을포함한혈액학적부작용과구역, 구토, 말초신경병증과같은주요합병증발생이기존 3주간격의항암화학요법에비해증가하지만생존율을향상시킬수있으므로, 임상적판단하에시행할수있다 ( 권고수준 2B, 근거표 3). 근거수준분석에포함된 3개의무작위배정연구중용량집중요법의유의한생존율증가를보고한연구는 1개뿐으로 (Katsumata 등, 2013) 22, 메타분석결과그유의성을입증하지못했지만, 연구들개별적분석을통해완결성이우수한 Katsumata 등의연구결과를바탕으로매주사용용량집중요법이생존율을향상시킬수있겠다고한부인종양전문가들의의견을권고수준에반영하였다. 근거수준과권고수준향상을위해현재진행중인무작위배정연구 (ICON8 또는 GOG262) 들의결과를확인할필요가있다. 본진료권고안에서추천하는우선적항암화학요법의용법은다음과같다 (Table 3). Table 3. Regimens of primary adjuvant chemotherapy Preferred regimens: 1. Paclitaxel 175 mg/m2 IV over 3 hours followed by carboplatin AUC 5 6 IV over 1 hour Day 1. Repeat every 3 weeks x 6 cycles. 2. Dose-dense paclitaxel 80 mg/m2 IV over 1 hour Days 1, 8, and 15 followed by carboplatin AUC 5 6 IV over 1 hour Day 1. Repeat every 3 weeks x 6 cycles. 10

13 3. Paclitaxel 60 mg/m2 IV over 1 hour followed by carboplatin AUC 2 IV over 30 minutes. Weekly for 18 weeks. 4. Docetaxel mg/m2 IV over 1 hour followed by carboplatin AUC 5 6 IV over 1 hour Day 1. Repeat every 3 weeks x 6 cycles. 5. Bevacizumab-containing regimens per ICON-7 and GOG-218: Paclitaxel 175 mg/m2 IV over 3 hours followed by carboplatin AUC 5 6 IV over 1 hour, and bevacizumab 7.5 mg/kg IV over minutes Day 1. Repeat every 3 weeks x 5 6 cycles. Continue bevacizumab for up to 12 additional cycles. (category 3) or Paclitaxel 175 mg/m2 IV over 3 hours followed by carboplatin AUC 6 IV over 1 hour Day 1. Repeat every 3 weeks x 6 cycles. Starting Day 1 of cycle 2, give bevacizumab 15 mg/kg IV over minutes every 3 weeks for up to 22 cycles Alternative regimens: Paclitaxel 135 mg/m2 IV continuous infusion over 3 or 24 h 3Day 1; cisplatin mg/m2 IP, Day 2 after IV paclitaxel; paclitaxel 60 mg/m2ip Day 8. Repeat every 3 weeks x 6 cycles. 약제및투여방식결정은환자의내과적질환유무, 독성, 전신상태 (performance status) 등을고려하여결정해야한다. Docetaxel/carboplatin 약제는상대적으로호중구감소증의발생을증가시키고, paclitaxel/carboplatin은말초신경독성의발생을증가시킨다. 당뇨환자와같이특히신경독성부작용이우려되는경우에는 docetaxel/carboplatin 용법을우선고려할수있다. 복강내투여용법은백혈구감소증, 감염, 피로, 신독성, 복부불편감및신경독성을유발시키고, 카테타관련합병증이빈번하기때문에, 6차례의항암요법을모두투여받는환자가 42% 에불과하다. 7 따라서, 전신상태가좋지않거나, 다른질환이있거나, 병기 IV인경우, 고령인경우는복강내투여가적절하지않다. 이외말초혈액줄기세포이식 (peripheral blood stem cell transplantation, PBST) 을이용한고용량항암화학요법은생존율의향상을보이지않았으므로, 아직까지는임상시험내에서만사용할것을권고한다 일차보조항암화학요법후의추가치료 1차보조요법시행후완전관해를보이지않는환자의경우, 재발성난소암에준하는치료가필요하다. 한편, 임상적완전관해를보이는환자의경우에는추적관찰을할수있다. 또, 일차치료후완전관해를보인환자에서의유지요법은 GOG 178 연구결과에근거하여투여될수있다. 이연구에서매달 paclitaxel을 175 mg/m2 용량으로 12개월동안투여받은환자군은 3개월투여한대조군에비해무병생존율의향상을보였다 ( 권고수준 2C). 또한, bevacizumab을 paclitaxel/carboplatin 과함께사용이후, 12-22주기동안추가유지함으로써무진행생존율을향상시킬수있다 ( 권고수준 2A, 근거표 4). 이차추시수술을시행할수도있는데, 생존율증가에기여한다는근거가없으므로잔류종양없는상태로수술이가능한경우에한하여선택적으로시행되어야한다 ( 근거수준 E). 이때, 잔류종양이관찰되는경우에는부분관해로판정하여재발성난소암에준하여치료하여야한다. 5. 추적관찰수술과항암화학요법후에는경과관찰을시행한다. 병력청취와진찰을포함한경과관찰은첫 2년간은 2-4개월간격으로, 그이후 3년간은 3-6개월간격으로, 그이후에는매년시행한다. 일반 11

14 부인암진료권고안 v.3.0 혈액검사를포함한기본검사와일반화학검사및흉부 X-선은필요한경우시행할수있다. 흉부 / 복부 / 골반 CT, MRI, PET 등도임상적으로필요한경우시행할수있다. CA-125를포함한종양표지자검사는처음에상승되어있었다면매방문시마다확인한다. 본진료권고안에서암의진행에관한정의는 GCIG (Gynecologic Cancer InterGroup) 기준에따르기로하였다 (Table 4). 9 난소암이호발하는소인과관련된유전자검사등을포함한유전상담의적응증에대해서는별도로발표될대한부인종양학회 position statement 를참고하기바란다. Table 4. Definition of progression after first-line therapy in ovarian cancer proposed by gynecologic cancer intergroup Patients group (definitions below) A B C Measurable/ nonmeasurable disease Compared to baseline (or lowest sum while on study if less than baseline), a 20% increase in sum of longest diameters (RECIST definition) or Any new lesions (measurable or nonmeasurable) Date PD: date of documentation of increase or new lesions And/or A B C CA-125 CA UNL documented two occasions* Date PD: first date of the CA-125 elevation to 2 UNL CA nadir value on two occasions* Date PD: first date of the CA-125 elevation to 2 nadir value As for A UNL; upper normal limit, PD; Progressive disease A; Patients with elevated CA-125 pretreatment and normalization of CA-125 (~60% of all new patients) B; Patients with elevated CA-125 pretreatment, which never normalizes (~30% of all new patients) C; Patients with CA-125 in normal range pretreatment (~10% of all new patients) *Repeat CA-125 anytime, but normally not less than 1 week after the first elevated level. CA-125 level sampled within 4 weeks after surgery, paracentesis, or administration of mouse antibodies should not be taken into account 6. 재발성난소암의치료치료후경과관찰중재발은대부분종양표지자상승과영상진단, 조직검사이상소견으로확인할수있다. 그러나일부환자중에서는 CA-125가증가하지만다른임상적재발의증거가없는경우가있다. 일반적으로 CA-125 증가후임상적재발까지는보통약 2-6개월의기간이걸리므로이러한경우재발에대한치료의시작시점에대해서는일치된의견이없다. 현재이러한환자의치료방침으로첫째종양재발의유일한증거로 CA-125만상승한경우임상시험을우선적으로고려할수있고, 임상적재발이확인될때까지치료를연기하거나 ( 권고수준 2D), 즉시항암화학요법을고려할수도있다 ( 권고수준 2D). 재발성난소암의치료는일반적으로치료종료후재발까지의기간에따라다음과같이결정한다. (1) 일차보조항암화학요법시행중진행성 / 안정성 / 지속성병변을보이는경우에임상시험또는재발치료를고려한다. (2) 일차보조항암화학요법으로완전관해에도달하였으나항암화학요법종료후 6개월이내에재 12

15 발된경우, 혹은병기 II-IV이면서일차항암화학요법시행후부분관해 ( 이차추시술에서암이확인된경우포함 ) 에도달한환자는임상시험또는재발용항암치료를고려한다. 백금저항성이있는환자에대해서 non-platinum계단독약제 (single non-platinum-based agent) 가권고된다. 재발성난소암에대한여러약제에대한반응률은 topotecan 20% 10, gemcitabine 19% 11, liposomal doxorubicin 26% 11,12, oral ectoposide 27% 13, belotecan (CKD-602) 20% 14, docetaxel 22% 15, irinotecan 29% 16, weekly paclitaxel 21% 17 로나타나고있다. 다른약제들로 vinorelbine, cyclophosphamide, melphalan 등이있다. 재발성또는지속성난소암환자에서 bevacizumab은 21% 반응율을보이고있다. 18 Version 2.0 이후추가된연구결과를바탕으로 bevacizumab과 paclitaxel/topotecan/liposomal doxorubicin 중한가지를함께사용하는병합표적치료가무진행생존율을유의하게향상시킬수있어, 고혈압, 장전공, 단백뇨와같은부작용이증가함에도불구하고, 사용할수있다 ( 권고등급 1). (3) 일차보조항암화학요법으로완전관해에도달하였으나치료종료후 6개월이후에재발한경우에백금민감성이있는것으로간주하여백금복합항암화학요법으로 carboplatin/paclitaxel 19, carboplatin/liposomal doxorubicin (6개월-1년사이재발한부분적백금민감성의경우특히우선사용고려 ) 20, carboplatin/gemcitabine/bevacizumab 21 ( 권고수준 2A, 근거표 4), carboplatin/weekly paclitaxel 22, carboplatin/docetaxel 23, carboplatin/gemcitabine 24, cisplatin/gemcitabine 24 을치료법으로고려할수있으며, 임상시험을적극적으로고려할수있다. 백금민감성이있으나복합요법치료를받을수없는경우는 carboplatin 또는 cisplatin 단독요법을시행할수있으며, oxaliplatin 도사용할수있다. 25 BRCA-관련난소암에서 PARP (poly[adp-ribose] polymerase) 억제제유지요법이생존율을향상시키는지에대한근거수준은매우낮고, PARP억제제사용군에서비사용군에비해구역, 호중구감소, 빈혈, 설사, 탈모, 말초신경병증과같은부작용이더많이발생하지만, BRCA 돌연변이가있는백금민감성재발성난소암환자에서유의한무진행생존율향상결과를바탕으로상기환자군에서 PARP억제제유지요법을시행한다. ( 근거수준 1D, 근거표 8) (4) 무병생존기간 (disease-free interval) 이 6개월이상비교적길고, 국소적재발또는용적이작은경우이차종양감축술을고려할수있다 ( 권고수준 2D, ver2.0). 26 이차종양감축술후상기항목에기술한 paclitaxel/carboplatin, gemcitabine/carboplatin, liposomal doxorbicin/carboplatin 등의복합항암요법또는재발성치료를고려할수있다. (5) 항암화학요법을견디지못하거나실패하였을경우호르몬치료 (tamoxifen, letrozole, anastrozole, leuprolide acetate, megestrol acetate) 가고려될수있으며 ( 근거수준 D), 방사선치료도사용될수있다 ( 근거수준 E). 조기에어떤약제를선택하든 2-4회투여후에반응을확인하며조기에 2가지연속적항암화학요법치료후효과없이진행하는환자에서는추가치료효과가낮을것으로생각된다. 이런경우항암치료를지속할것인지새로운약제를대상으로한임상시험에들어갈지에대한판단은환자의개별적상태에따라이루어져야할것이다. 13

16 부인암진료권고안 v.3.0 III. 경계성상피성난소종양 1. 진단및치료경계성난소종양은병리조직학적소견상악성세포변화를보이지만명백한침윤이없고임상적으로천천히자라는상피성난소종양으로, 5년생존율이 80% 를넘을정도로예후가좋다. 경계성난소종양은젊은연령에서조기병변으로발견되는경우가많다. 침윤성착상병변 (invasive implants) 이있는경우예후가좋지않다는보고들을바탕으로일부에서는수술후항암화학요법을고려하지만, 수술후항암화학요법이효과에대해서는아직논란의여지가있다. 특히, 침윤성착상이없는경우수술후항암화학요법의효과는보고된바없어, 수술후추가치료없이추적관찰하는것이추천된다. 치료는병리조직학적특징, 나이, 병기에따라다르다. (1) 골반종양으로수술시경계성난소종양으로확인된경우, 임신을원하는경우임신능력보존수술및포괄적병기결정수술을시행하고, 임신을원치않는다면완전한병기결정수술을시행한다. 장액성경계성종양의경우완전한병기결정수술이불완전병기결정수술에비하여생존율을향상시키는지에대해서는아직까지정확한결론을내리기에그근거가부족한실정이다 ( 권고등급 E, 근거표 6). 수술결과침윤성착상병변이없거나비침윤성착상병변만있는경우추가치료없이관찰한다. 27 수술결과침윤성착상병변이있는경우관찰하거나, 상피성난소암과같이보조항암화학요법을시행할수있다 ( 권고수준 2C). (2) 이미수술로경계성난소종양이진단된경우에는병리조직검사를재검토한다. 이전수술시완전한병기결정수술이시행되었다면전술한바와같이치료를하고, 불완전한병기설정수술이시행되었다면잔류종양의존재에따라치료가달라지게된다. 잔류종양이의심되는경우, 임신을원한다면추가치료없이관찰 ( 침윤성착상없거나모를경우 ) 또는임신능력보존수술을포함한완전한병기설정수술을시행하는것 ( 침윤성착상이있는경우 ) 이추천된다. 불완전한병기설정수술이었다고하더라도잔류종양이의심되지않는경우에는추가치료없이관찰할수있다. 2. 관찰및재발암의치료치료후에는경과관찰을시행한다. 병력청취와골반진찰을포함한경과관찰은첫 2년은 2-4 개월간격, 이후 3년간은 3-6개월간격, 이후에는매년시행한다. 일반혈액검사를포함한기본실험실검사와일반화학검사및흉부 X-선은필요한경우시행할수있다. 임신능력보존수술을시행받은환자의경우는필요한경우골반초음파검사를시행한다. 흉부 / 복부 / 골반 CT, MRI, PET 등도임상적으로필요한경우시행할수있다. CA-125를포함한종양표지자검사는처음부터높았다면매방문시마다확인한다. 본진료권고안에서 CA-125 증가의정의는 GCIG 기준에따르기로하였다 (Table 4). 난소암이호발하는소인과관련된유전자검사등을포함한유전상담의적응증에대해서는별도로발표된대한부인종양학회 position statement 를참고하기바란다. 추적관찰중에임상적으로재발이확인될경우진단적수술과함께가능하다면종양감축술을고려한다. 수술결과침윤성착상병변이있는경우에는상피성난소암에준한치료를고려하거나 ( 권고수준 2C), 추가치료없이관찰할수있다. 침윤성암종 (invasive carcinoma, low or high grade) 이발견된경우에는상피성난소암과같이치료하는것이추천된다. 침윤성착상병변이없는경우에는경과관찰만하면된다. 14

17 IV. 기타난소암 상피성난소암이외에생식세포종양, 암육종 (carcinosarcoma, malignant mixed müllerian tumors), 성삭간질종양 (sex cord stromal tumor) 등이난소암에포함된다. 이러한종양은전체난소암의약 5% 를차지하고그생물학적행태나치료방침에있어상피성난소암과차이가있다. 이러한난소암은상피성난소암과달리대부분어린나이에발견되고한쪽난소에국한된조기에서진단되기때문에, 임신능력보존수술의대상이되는경우가많고, 이때복강경을이용한최소침습수술도고려할수있다 진단검사병리조직학적진단이되지않은골반종양의경우진단을위하여선택적으로기본검사, 초음파, CT, MRI 혹은 PET 등을시행한다. 또한필요에따라선별적종양표지자 (CA-125, inhibin, AFP, β -hcg, LDH) 검사를시행한다. 임신능력을보존하고자하는환자는수술중동결절편검사가필요하다. 수술소견상조기병변이면서동결절편검사에서생식세포종양혹은 low malignant potential을가진난소암일경우는임신능력보존수술을시행할수있다. 29 임신을원하지않거나, 임상병기고위험 II, III, IV의상피성난소암또는성삭기질종양이거나, 암육종일경우는상피성난소암과같이완전한병기설정수술을시행해야한다. I기미분화세포종 (dysgerminoma) 또는 I 기, 분화도 1 미성숙기형종 (immature teratoma) 이아닌생식세포종양도수술을시행한다. 이전수술로인해이미조직학적으로진단된후내원하는환자의경우의수술은조직학적진단과이전수술내용에따라달라진다. 2. 진단및치료 (1) 생식세포종양생식세포종양의진단을위한검사로는기본검사, CA-125, Inhibin, LDH (lactic dehydrogenase), AFP, 그리고 β-hcg 수치, 초음파혹은복부골반 CT, MRI 혹은 PET을시행하고추가적으로폐기능검사를시행할수있다 ( 권고수준 1C). 임신을원치않는경우에는완전한병기결정수술을시행하지만, 임신을원하는경우병기와상관없이임신능력보존수술을고려해야한다. 악성생식세포종양은매우예후가좋아, 적절한치료를받는다면 5년생존율은 85% 이상이다. 수술후필요에따라서초음파검사로추적관찰을시행하고, 자녀계획이완성된시기에완전한수술을시행하는것이고려되어야한다. 완전한병기결정수술이시행된 I기미분화배세포종이나 I기분화도1의미성숙기형종은경과관찰만시행한다. 병기결정수술이완전하지않았을경우에는경과관찰만하거나다시병기결정수술을시행할수있다 ( 권고수준 2C). 성인에서와달리, 소아또는청소년기의조기생식세포종양에서는완전한병기설정수술이생략될수도있다. 30,31 수술후잔류종양의증거가없는경우에는경과관찰만하지만잔류종양이있을경우에는수술후 bleomycin/etoposide/platinum (BEP) 병합요법을시행한다. Bleomycin 사용을고려하는경우에는폐기능검사를추천한다. 만약내과적인이유등으로 bleomycin을사용할수없는경우에는 vin-cristine/dactinomycin/cyclophosphamide (VAC) 병합요법이고려될수있다 ( 권고수준 1C). 배아암종 (embryonal carcinoma) 혹은난황막종양 (yolk sac tumor) 이거나, 병기 II-IV의미분화배세 15

18 부인암진료권고안 v.3.0 포종, 혹은 I기, 분화도 2-3의미성숙기형종인경우에는 3-4회의 BEP 병합요법을시행한다. 병기 IB-III의미분화세포종이고 BEP의부작용이우려되는환자에서는 3회의 etoposide/carboplatin 병합요법을투여한다. 항암화학요법후완전관해를보인환자는 2년간 2-4개월간격으로경과관찰을하는데치료전종양표지자가상승되어있던환자는동일한종양표지자검사를반복한다. 영상진단상으로잔류종양이남아있고종양표지자검사가정상범위일때는수술적제거를고려하거나경과관찰을시행할수있다. 일차항암화학요법후에도지속적으로종양표지자가상승되거나병변의진행이의심될때는 TIP (paclitaxel/ifosfamide/cisplatin) 나고용량항암화학요법이추천된다. 이외재발암에대한구제요법은다음과같다 : VP (cisplatin/etoposide), VIP (etoposide/ifosfamide/cisplatin), VeIP (vinblastine/ifosfamide/cisplatin), VAC (vincristine/ dactinomycin/cyclophosphamide), docetaxel, paclitaxel, 방사선요법. (2) 성삭간질종양병기 IA-C이고임신을원하는환자는임신능력보존수술을시행한다. 그외의모든환자는완전한병기결정수술을시행한다. 수술소견상병기 I이며저위험군인경우에는경과관찰을시행한다. 병기 I이고고위험군 ( 종양파열, 세포분화도 3, 종양크기 cm 이상 ) 인경우는경과관찰을시행하거나, 방사선요법, cisplatin 병합항암화학요법등을선택적으로고려할수있다 ( 권고수준 2C). 병기 II-IV인경우제한된국소병변일때는방사선치료를하거나백금포함복합항암화학요법 ( 생식세포종양에서사용되는요법이나 paclitaxel/carboplatin 요법이선호됨 ) 을시행할수있다 ( 권고수준 2C). 재발암의경우에는다음과같은치료방법이시행될수있다 : 임상시험, 대증요법, 항암화학요법 ( 생식세포종양에서사용되는요법이나 paclitaxel/carboplatin 요법이선호됨 ), leuprolide, 이차종양감축술. (3) 암육종완전한병기결정수술로병기 I로진단된경우는상피성난소암에준하는항암화학요법을선택적으로시행할수있다. 병기 II-IV와재발성인경우에는상피성난소암과같이치료한다. 16

19 V. 요약 17

20 부인암진료권고안 v

21 19

22 부인암진료권고안 v

23 21

24 부인암진료권고안 v

25 VI. 참고문헌 1. Walker JL, Powell CB, Chen LM, et al. Society of Gynecologic Oncology recommendations for the prevention of ovarian cancer. Cancer [Epub ahead of print] 2. Falconer H, Yin L, Gronberg H, Altman D. Ovarian cancer risk after salpingectomy: a nationwide population-based study. J Natl Cancer Inst. 2015; 107(2). 3. Kwon JS, Tinker A, Pansegrau G, et al. Prophylactic salpingectomy and delayed oophorectomy as an alternative for BRCA mutation carriers. Obstet Gynecol. 2013; 121(1): Chi DS, Eisenhauer EL, Zivanovic O, et al. Improved progression-free and overall survival in advanced ovarian cancer as a result of a change in surgical paradigm. Gynecol Oncol. 2009; 114(1): Kehoe S, Hook J, Nankivell M, et al. Primary chemotherapy versus primary surgery for newly diagnosed advanced ovarian cancer (CHORUS): an open-label, randomised, controlled, non-inferiority trial. Lancet. 2015; 386(9990): Vergote I, Trope CG, Amant F, et al. Neoadjuvant chemotherapy or primary surgery in stage IIIC or IV ovarian cancer. N Engl J Med. 2010; 363(10): Walker JL, Armstrong DK, Huang HQ, et al. Intraperitoneal catheter outcomes in a phase III trial of intravenous versus intraperitoneal chemotherapy in optimal stage III ovarian and primary peritoneal cancer: a Gynecologic Oncology Group Study. Gynecol Oncol. 2006; 100(1): Mobus V, Wandt H, Frickhofen N, et al. Phase III trial of high-dose sequential chemotherapy with peripheral blood stem cell support compared with standard dose chemotherapy for first-line treatment of advanced ovarian cancer: intergroup trial of the AGO-Ovar/AIO and EBMT. J Clin Oncol. 2007; 25(27): Vergote I, Rustin GJ, Eisenhauer EA, et al. Re: new guidelines to evaluate the response to treatment in solid tumors [ovarian cancer]. Gynecologic Cancer Intergroup. J Natl Cancer Inst. 2000; 92(18): Gordon AN, Tonda M, Sun S, Rackoff W, Doxil Study I. Long-term survival advantage for women treated with pegylated liposomal doxorubicin compared with topotecan in a phase 3 randomized study of recurrent and refractory epithelial ovarian cancer. Gynecol Oncol. 2004; 95(1): Mutch DG, Orlando M, Goss T, et al. Randomized phase III trial of gemcitabine compared with pegylated liposomal doxorubicin in patients with platinum-resistant ovarian cancer. J Clin Oncol. 2007; 25(19): Ferrandina G, Ludovisi M, Lorusso D, et al. Phase III trial of gemcitabine compared with pegylated liposomal doxorubicin in progressive or recurrent ovarian cancer. J Clin Oncol. 2008; 26(6): Rose PG, Blessing JA, Mayer AR, Homesley HD. Prolonged oral etoposide as second-line therapy for platinum-resistant and platinum-sensitive ovarian carcinoma: a Gynecologic Oncology Group study. J Clin Oncol. 1998; 16(2): Lee HP, Seo SS, Ryu SY, et al. Phase II evaluation of CKD-602, a camptothecin analog, administered on a 5-day schedule to patients with platinum-sensitive or -resistant ovarian cancer. Gynecol Oncol. 2008; 109(3): Markman M, Hakes T, Reichman B, et al. Ifosfamide and mesna in previously treated advanced epithelial ovarian cancer: activity in platinum-resistant disease. J Clin Oncol. 1992; 10(2): Matsumoto K, Katsumata N, Yamanaka Y, et al. The safety and efficacy of the weekly dosing of irinotecan for platinumand taxanes-resistant epithelial ovarian cancer. Gynecol Oncol. 2006; 100(2): Miller DS, Blessing JA, Krasner CN, et al. Phase II evaluation of pemetrexed in the treatment of recurrent or persistent platinum-resistant ovarian or primary peritoneal carcinoma: a study of the Gynecologic Oncology Group. J Clin Oncol. 2009; 27(16): Burger RA, Sill MW, Monk BJ, Greer BE, Sorosky JI. Phase II trial of bevacizumab in persistent or recurrent epithelial ovarian cancer or primary peritoneal cancer: a Gynecologic Oncology Group Study. J Clin Oncol. 2007; 25(33):

26 부인암진료권고안 v Parmar MK, Ledermann JA, Colombo N, et al. Paclitaxel plus platinum-based chemotherapy versus conventional platinum-based chemotherapy in women with relapsed ovarian cancer: the ICON4/AGO-OVAR-2.2 trial. Lancet. 2003; 361(9375): Power P, Stuart G, Oza A, et al. Efficacy of pegylated liposomal doxorubicin (PLD) plus carboplatin in ovarian cancer patients who recur within six to twelve months: a phase II study. Gynecol Oncol. 2009; 114(3): Aghajanian C, Blank SV, Goff BA, et al. OCEANS: a randomized, double-blind, placebo-controlled phase III trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer. J Clin Oncol. 2012; 30(17): Katsumata N, Yasuda M, Takahashi F, et al. Dose-dense paclitaxel once a week in combination with carboplatin every 3 weeks for advanced ovarian cancer: a phase 3, open-label, randomised controlled trial. Lancet. 2009; 374(9698): Strauss HG, Henze A, Teichmann A, et al. Phase II trial of docetaxel and carboplatin in recurrent platinum-sensitive ovarian, peritoneal and tubal cancer. Gynecol Oncol. 2007; 104(3): Pfisterer J, Plante M, Vergote I, et al. Gemcitabine plus carboplatin compared with carboplatin in patients with platinum-sensitive recurrent ovarian cancer: an intergroup trial of the AGO-OVAR, the NCIC CTG, and the EORTC GCG. J Clin Oncol. 2006; 24(29): Dieras V, Bougnoux P, Petit T, et al. Multicentre phase II study of oxaliplatin as a single-agent in cisplatin/carboplatin +/- taxane-pretreated ovarian cancer patients. Ann Oncol. 2002; 13(2): Eisenkop SM, Friedman RL, Spirtos NM. The role of secondary cytoreductive surgery in the treatment of patients with recurrent epithelial ovarian carcinoma. Cancer. 2000; 88(1): Kennedy AW, Hart WR. Ovarian papillary serous tumors of low malignant potential (serous borderline tumors). A long-term follow-up study, including patients with microinvasion, lymph node metastasis, and transformation to invasive serous carcinoma. Cancer. 1996; 78(2): Fischerova D, Zikan M, Dundr P, Cibula D. Diagnosis, treatment, and follow-up of borderline ovarian tumors. Oncologist. 2012; 17(12): Zanetta G, Bonazzi C, Cantu M, et al. Survival and reproductive function after treatment of malignant germ cell ovarian tumors. J Clin Oncol. 2001; 19(4): Mahdi H, Swensen RE, Hanna R, et al. Prognostic impact of lymphadenectomy in clinically early stage malignant germ cell tumour of the ovary. Br J Cancer. 2011; 105(4): Billmire D, Vinocur C, Rescorla F, et al. Outcome and staging evaluation in malignant germ cell tumors of the ovary in children and adolescents: an intergroup study. J Pediatr Surg. 2004; 39(3): 424-9; discussion

27 [ 부록 1] 의핵심질문및 PICO* * PICO: Population (P), Intervention or indicator (I), Comparator (C), Outcome (O) [KQ 1] 임상적으로난소에국한된조기상피성난소암환자에서체계적골반그리고 / 또는대 동맥주위림프절절제술 (systemic pelvic and/or paraaortic lymphadenectomy) 은생존율을 향상시키는가?? P : Clinical stage I, epithelial ovarian cancer I : Systemic lymphadenectomy C : No lymphadenectomy or selective lymphadenectomy O : Overall survival or Progression-free survival [KQ 2] 최적종양감축 (optimal cytoreduction) 이어려울것으로판단되는진행성상피성난소암에서선행화학요법후종양감축술 (interval cytoreductive surgery) 이일차종양감축술 (primary cytoreductive surgery) 에비해생존율에차이가없는가? P : Advanced stage epithelial ovarian cancer I : Neoadjuvant chemotherapy followed by interval cytoreductive surgery C : Primary cytoreductive surgery O : Overall survival or Progression-free survival [KQ 3] 진행성상피성난소암에서일차용량집중항암화학요법 (first-line dose-dense chemotherapy) 는생존율을향상시키는가? P : Advanced stage epithelial ovarian cancer I : Dose-dense paclitaxel/carboplatin C : Triweekly paclitaxel/carboplatin O : Overall survival or Progression-free survival [KQ 4] 상피성난소암환자에서수술후일차 (first-line) 및재발시이차 (second-line) 치료로서 bevacizumab 이생존율을향상시키는가? P : Postoperative first-line and recurrent setting in epithelial ovarian cancer I : Chemotherapy with bevacizumab C : Chemotherapy without bevacizumab O : Overall survival or Progression-free survival 25

28 부인암진료권고안 v.3.0 [KQ 5] 자궁부속기종양이있는환자에서 ROMA 는난소암감별진단의민감도와특이도에있 어서 CA-125 보다우수한가? P : Patients with adnexal mass I : CA-125 and HE4 combination (ROMA) C : CA-125 O : Diagnostic sensitivity and specificity for detecting ovarian cancer [KQ 6] 장액성경계성난소종양 (Serous borderline ovarian tumor) 에서포괄적병기설정술이생존율을향상시키는가? P : Borderline ovarian tumor (serous vs. mucinous) I : Full staging operation C : Incomplete staging operation O : Overall survival or Progression-free survival [KQ 7] 향후임신을원하는젊은조기상피성난소암환자에서임신능력보존수술 (fertilitysparing surgery) 은생존율에영향을미치는가? P : Clinical stage I epithelial ovarian cancer I : USO with comprehensive staging C : Hysterectomy and BSO with comprehensive staging O : Overall survival or Progression-free survival [KQ 8] BRCA-관련난소암 (BRCA-associated ovarian cancer) 에서 PARP 억제제유지요법은생존율을향상시키는가? P : Ovarian cancer patients with or without BRCA mutation I : PARP inhibitor maintenance therapy C : No PARP inhibitor maintenance therapy O : Overall survival or Progression-free survival 26

29 [ 부록 2] 의핵심질문및개별참고문헌 [KQ 1] 핵심질문 질문 : 임상적으로난소에국한된조기상피성난소암환자에서체계적골반그리고 / 또는대동맥주위림프절절제술 (systemic pelvic and/or paraaortic lymphadenectomy) 은생존율을향상시키는가? [KQ 1] 임상적으로난소에국한된조기상피성난소암환자에서체계적골반그리고 / 또는대동맥주위림프절절제술시행은미시행또는선택적절제술에비해생존율을유의하게향상시킨다는근거가부족하나, 임상적판단하에시행할수있다. [Level 2B] ( 권고등급 2=weak; 근거수준 B=moderate) 1-2. 문헌검색문헌검색은 Pubmed, Embase, Cochrane을이용하였으며, 검색식은아래와같다. Table 1. Procedure used for MEDLINE, EMBASE, and COCHRANE to identify eligible clinical studies for answering KQ1 MEDLINE 1. "Ovarian Neoplasms"[Mesh:NoExp] Ovarian[tiab] OR Ovary[tiab] OR Ovaries[tiab] OR adnexa[tiab] OR adnexal[tiab] "adnexa uteri"[mesh] OR "Ovary"[Mesh] OR cancer[tiab] OR malignant[tiab] OR carcinoma[tiab] OR neoplasm[tiab] OR cancers[tiab] OR malignancy[tiab] OR carcinomas[tiab] OR neoplasms[tiab] OR Adenocarcinoma[tiab] OR Adenocarcinomas[tiab] ("Adenocarcinoma"[Mesh]) OR "Carcinoma, Endometrioid"[Mesh] OR AND OR "Lymph Nodes"[Mesh:NoExp] "lymph node"[tiab] OR "lymph nodes"[tiab] OR excision[tiab] OR excisions[tiab] OR resec*[tiab] OR operation[tiab] OR surgery[tiab] OR surgical[tiab] OR dissection[tiab] OR operative[tiab] OR dissections[tiab] AND lymphadenectomy[tiab] OR Lymphadenectomies[tiab] lymph node excision"[mesh:noexp] OR 15 OR AND EMBASE 1. 'ovary cancer'/de OR 'ovary adenocarcinoma'/exp OR 'ovary carcinoma'/exp OR 'ovary metastasis'/exp Ovarian:ab,ti OR Ovary:ab,ti OR Ovaries:ab,ti OR adnexa:ab,ti OR adnexal:ab,ti 'ovary'/exp OR cancer:ab,ti OR malignant:ab,ti OR carcinoma:ab,ti OR neoplasm:ab,ti OR cancers:ab,ti OR malignancy:ab,ti OR carcinomas:ab,ti OR neoplasms:ab,ti OR Adenocarcinoma:ab,ti OR Adenocarcinomas:ab,ti

30 부인암진료권고안 v 'endometrioid carcinoma'/exp OR AND OR 'lymph node'/de OR 'paraaortic lymph node'/exp OR 'pelvis lymph node'/exp 'lymph node':ab,ti OR 'lymph nodes':ab,ti OR excision:ab,ti OR excisions:ab,ti OR resec*:ab,ti OR operation:ab,ti OR surgery:ab,ti OR surgical:ab,ti OR dissection:ab,ti OR operative:ab,ti OR dissections:ab,ti AND lymphadenectomy:ab,ti OR Lymphadenectomies:ab,ti 'lymph node dissection'/exp OR 15 OR AND NOT ('editorial'/it OR 'erratum'/it OR 'letter'/it OR 'note'/it OR 'short survey'/it) NOT ('human cell'/de OR 'nonhuman'/de) 3469 COCHRANE 1. MeSH descriptor: [Ovarian Neoplasms] this term only Ovarian OR Ovary OR Ovaries OR adnexa OR adnexal:ab,ti,kw MeSH descriptor: [Adnexa Uteri] explode all trees" MeSH descriptor: [Ovary] explode all trees 975 cancer OR malignant OR carcinoma OR neoplasm OR cancers OR malignancy OR carcinomas OR neoplasms OR Adenocarcinoma OR Adenocarcinomas:ab,ti,kw MeSH descriptor: [Adenocarcinoma] explode all trees MeSH descriptor: [Carcinoma, Endometrioid] explode all trees 32 1 or ((2 or 3 or 4) and (5 or 6 or 7)) /trail 3209 상기방법을이용하여검색하였을때, 총 4,354개의논문이검색되었다. 이논문들을아래와같은 inclusion 및 exclusion criteria를적용하여, 최종적으로 5개의논문을선정하였다. Figure 1. Flow chart of searching strategy for answering KQ1 28

31 1-3. 문헌평가최종선정된 5개의논문은 1개의 RCT 와 4개의 NRS 연구이었으며, risk of bias 평가를위하여각각 Quality Assessment of Diagnostic Accuracy Studies (QUADAS) 와 Ottawa Quality Assessment Scale을사용하였다 근거수준과권고등급결정을위한내용및근거 29

32 부인암진료권고안 v.3.0 본핵심질문에대한근거는 RCT 가 1 개밖에없으나, 4 개의 NRS 와함께모두일관된결과를 지지하고있음. RRR=0.14, 대조군의사망위험 20%, 을고려하면 OIS>800 이어야하나, 사망자수는 47 명으로정확성이입증되지않음. ( 근거수준 : MODERATE) 1-5. 메타분석본권고안에서는조기상피성난소암환자에서 systemic pelvic and/or paraaortic lymphadenectomy 이 no lymphadenectomy or LN sampling 에비해생존율을향상시키는지를확인하기위하여메타분석함. 그결과, systemic pelvic and/or paraaortic lymphadenectomy 는 no lymphadenectomy or LN sampling 에비해생존율을향상시키나, RCT 결과통계적유의성을확인하지못함 참고문헌 [KQ1] 1. Maggioni A, Benedetti Panici P, Dell'Anna T, et al. Randomised study of systematic lymphadenectomy in patients with epithelial ovarian cancer macroscopically confined to the pelvis. British journal of cancer. Sep ;95(6): Chan JK, Munro EG, Cheung MK, et al. Association of lymphadenectomy and survival in stage I ovarian cancer patients. Obstetrics and gynecology. Jan 2007;109(1): Suzuki S, Kajiyama H, Shibata K, et al. Is there any association between retroperitoneal lymphadenectomy and survival benefit in ovarian clear cell carcinoma patients? Annals of oncology : official journal of the European Society for Medical Oncology / ESMO. Jul 2008;19(7): Oshita T, Itamochi H, Nishimura R, et al. Clinical impact of systematic pelvic and para-aortic lymphadenectomy for pt1 and pt2 ovarian cancer: a retrospective survey by the Sankai Gynecology Study Group. International journal of clinical oncology. Dec 2013;18(6): Svolgaard O, Lidegaard O, Nielsen ML, et al. Lymphadenectomy in surgical stage I epithelial ovarian cancer. Acta obstetricia et gynecologica Scandinavica. Mar 2014;93(3):

33 [KQ 2] 핵심질문 질문 : 최적종양감축 (optimal cytoreduction) 이어려울것으로판단되는진행성상피성난소암에서선행화학요법후종양감축술 (interval cytoreductive surgery) 이일차종양감축술 (primary cytoreductive surgery) 에비해생존율에차이가없는가? [KQ 2] 최적종양감축 (optimal cytoreduction) 이어려울것으로판단되는진행성상피성난소암에서선행화학요법후종양감축술이일차종양감축술과비교하여생존율에차이가없으므로, 시행할수있다. [Level 2A] ( 권고등급 2=weak; 근거수준 A=high) 2-2. 문헌검색문헌검색은 Pubmed, Embase, Cochrane을이용하였으며, 검색식은아래와같다. Table 1. Procedure used for MEDLINE, EMBASE, and COCHRANE to identify eligible clinical trials for answering KQ2 MEDLINE EMBASE 1. "Ovarian Neoplasms"[Mesh:NoExp] Ovarian[tiab] OR Ovary[tiab] OR Ovaries[tiab] OR adnexa[tiab] OR adnexal[tiab] "adnexa uteri"[mesh] OR "Ovary"[Mesh] OR cancer[tiab] OR malignant[tiab] OR carcinoma[tiab] OR neoplasm[tiab] OR cancers[tiab] OR malignancy[tiab] OR carcinomas[tiab] OR neoplasms[tiab] OR Adenocarcinoma[tiab] OR Adenocarcinomas[tiab] ("Adenocarcinoma"[Mesh]) OR "Carcinoma, Endometrioid"[Mesh] OR AND OR neoadjuvant[tiab] OR preoperative[tiab] OR peri-operative[tiab] OR "peri operative"[tiab] OR pre-operative[tiab] OR "pre operative"[tiab] OR perioperative[tiab] OR "Neoadjuvant Therapy"[Mesh] ((Antineoplastic[tiab] OR Antineoplastics[tiab] OR "Anti neoplastic"[tiab] OR "Anti-neoplastic"[tiab]OR Antineoplastically[tiab] OR Chemotherapeutic[tiab] OR Anticancer[tiab] OR Chemotherapy[tiab] OR Anti-cancer[tiab] OR "Anti cancer"[tiab] OR Chemotheraphy[tiab] OR Chemotherapic[tiab] OR Chemotherapies[tiab] OR "Chemo therapy"[tiab] OR "Chemo-therapy"[tiab])) OR ((("Antineoplastic Agents"[Mesh]) OR "Antineoplastic Agents" [Pharmacological Action]) OR "Antineoplastic Combined Chemotherapy Protocols"[Mesh]) AND AND 'ovary cancer'/de OR 'ovary adenocarcinoma'/exp OR 'ovary carcinoma'/exp OR 'ovary metastasis'/exp Ovarian:ab,ti OR Ovary:ab,ti OR Ovaries:ab,ti OR adnexa:ab,ti OR adnexal:ab,ti 'ovary'/exp OR cancer:ab,ti OR malignant:ab,ti OR carcinoma:ab,ti OR neoplasm:ab,ti OR cancers:ab,ti OR malignancy:ab,ti OR carcinomas:ab,ti OR neoplasms:ab,ti OR Adenocarcinoma:ab,ti OR Adenocarcinomas:ab,ti 'endometrioid carcinoma'/exp

34 부인암진료권고안 v OR AND OR Antineoplastic:ab,ti OR Antineoplastics:ab,ti OR 'Anti neoplastic':ab,ti OR 'Anti-neoplastic':ab,ti OR Antineoplastically:ab,ti OR Chemotherapeutic:ab,ti OR Anticancer:ab,ti OR Chemotherapy:ab,ti OR Anti-cancer:ab,ti OR 'Anti cancer':ab,ti OR Chemotheraphy:ab,ti OR Chemotherapic:ab,ti OR Chemotherapies:ab,ti OR 'Chemo therapy':ab,ti OR 'Chemo-therapy':ab,ti 'antineoplastic agent'/exp OR 'chemotherapy'/exp OR neoadjuvant:ab,ti OR preoperative:ab,ti OR peri-operative:ab,ti OR 'peri operative':ab,ti OR pre-operative:ab,ti OR 'pre operative':ab,ti OR perioperative:ab,ti AND AND NOT ('nonhuman'/de OR 'editorial'/it OR 'erratum'/it OR 'letter'/it OR 'note'/it OR 'short survey'/it) 1885 COCHRANE 1. MeSH descriptor: [Ovarian Neoplasms] this term only Ovarian OR Ovary OR Ovaries OR adnexa OR adnexal:ab,ti,kw MeSH descriptor: [Adnexa Uteri] explode all trees" MeSH descriptor: [Ovary] explode all trees cancer OR malignant OR carcinoma OR neoplasm OR cancers OR malignancy OR carcinomas OR neoplasms OR Adenocarcinoma OR Adenocarcinomas:ab,ti,kw MeSH descriptor: [Adenocarcinoma] explode all trees MeSH descriptor: [Carcinoma, Endometrioid] explode all trees or ((2 or 3 or 4) and (5 or 6 or 7)) /trail 3209 상기방법을이용하여검색하였을때, 총 2,335개의논문이검색되었다. 이논문들을아래와같은 inclusion 및 exclusion criteria를적용하여, 최종적으로 7개의논문을선정하였다. Figure 1. Flow chart of searching strategy for answering KQ2 32

35 2-3. 문헌평가최종선정된 7개의논문은 2개의 RCT 와 5개의 NRS 연구이었으며, risk of bias 평가를위하여각각 Quality Assessment of Diagnostic Accuracy Studies (QUADAS) 와 Ottawa Quality Assessment Scale을사용하였다. 33

36 부인암진료권고안 v 근거수준과권고등급결정을위한내용및근거 본핵심질문에대한근거는 2개의 RCT 연구결과에의해지지되었음. RRR=0.06, 사망위험 =99%, OIS<200인데, 사망자수 >1,000 이므로 NAC groups 이 PS group 에비해 6% 의생존이득이있으나통계적으로유의하지않음 ( 근거수준 : HIGH) 34

37 Estimation of GRADE 2-5. 메타분석본권고안에서는진행성상피성난소암에서선행화학요법후 interval cytoreductive surgery를시행하는것이 primary cytoreductive surgery 에비해생존율을향상시키는지를확인하기위하여메타분석을시행하였다. 그결과, 두그룹간의생존율에유의한차이를확인하지못했다. Figure 2. Result of meta-analysis 2-6. 참고문헌 [KQ2] 1. Vergote I, Trope CG, Amant F, et al. Neoadjuvant chemotherapy or primary surgery in stage IIIC or IV ovarian cancer. The New England journal of medicine. Sep ;363(10): Kehoe S, Hook J, Nankivell M, et al. Primary chemotherapy versus primary surgery for newly diagnosed advanced ovarian cancer (CHORUS): an open-label, randomised, controlled, non-inferiority trial. Lancet. Jul ;386(9990): Everett EN, French AE, Stone RL, et al. Initial chemotherapy followed by surgical cytoreduction for the treatment of stage III/IV epithelial ovarian cancer. American journal of obstetrics and gynecology. Aug 2006;195(2): ; discussion Hou JY, Kelly MG, Yu H, et al. Neoadjuvant chemotherapy lessens surgical morbidity in advanced ovarian cancer and leads to improved survival in stage IV disease. Gynecologic oncology. Apr 2007;105(1): Worley MJ, Jr., Guseh SH, Rauh-Hain JA, et al. Does neoadjuvant chemotherapy decrease the risk of hospital readmission following cytoreductive surgery? Gynecologic oncology. Apr 2013;129(1): Glasgow MA, Yu H, Rutherford TJ, et al. Neoadjuvant chemotherapy (NACT) is an effective way of managing elderly women with advanced stage ovarian cancer (FIGO Stage IIIC and IV). Journal of surgical oncology. Feb 2013;107(2): Fago-Olsen CL, Ottesen B, Kehlet H, et al. Does neoadjuvant chemotherapy impair long-term survival for ovarian cancer patients? A nationwide Danish study. Gynecologic oncology. Feb 2014;132(2):

38 부인암진료권고안 v.3.0 [KQ 3] 핵심질문 질문 : 진행성상피성난소암에서수술후일차용량집중항암화학요법 (first-line dose-dense chemotherapy) 은생존율을향상시키는가? [KQ 3] 진행성상피성난소암에서수술후일차용량집중항암화학요법은기존의표준항암화학요법에비해독성이높으나생존율을유의하게향상시킬수있으므로, 임상적판단하에시행할수있다. [Level 2B] ( 권고등급 2=weak; 근거수준 B=moderate) 3-2. 문헌검색문헌검색은 Pubmed, Embase, Cochrane을이용하였으며, 검색식은아래와같다. Table 1. Procedure used for MEDLINE, EMBASE, and COCHRANE to identify eligible clinical trials for answering KQ3 MEDLINE 1. "Ovarian Neoplasms"[Mesh:NoExp] Ovarian[tiab] OR Ovary[tiab] OR Ovaries[tiab] OR adnexa[tiab] OR adnexal[tiab] "adnexa uteri"[mesh] OR "Ovary"[Mesh] OR cancer[tiab] OR malignant[tiab] OR carcinoma[tiab] OR neoplasm[tiab] OR cancers[tiab] OR malignancy[tiab] OR carcinomas[tiab] OR neoplasms[tiab] OR Adenocarcinoma[tiab] OR Adenocarcinomas[tiab] ("Adenocarcinoma"[Mesh]) OR "Carcinoma, Endometrioid"[Mesh] OR AND OR ((Antineoplastic[tiab] OR Antineoplastics[tiab] OR "Anti neoplastic"[tiab] OR "Anti-neoplastic"[tiab]OR Antineoplastically[tiab] OR Chemotherapeutic[tiab] OR Anticancer[tiab] OR Chemotherapy[tiab] OR Anti-cancer[tiab] OR "Anti cancer"[tiab] OR Chemotheraphy[tiab] OR Chemotherapic[tiab] OR Chemotherapies[tiab] OR "Chemo therapy"[tiab] OR "Chemo-therapy"[tiab])) OR ((("Antineoplastic Agents"[Mesh]) OR "Antineoplastic Agents" [Pharmacological Action]) OR "Antineoplastic Combined Chemotherapy Protocols"[Mesh]) dose-dense[tiab] OR triweekly[tiab] OR weekly[tiab] OR "dose dense"[tiab] AND ("Paclitaxel"[Mesh] OR paclitaxel[tiab] OR Taxol[tiab]) AND ("Carboplatin"[Mesh] OR carboplatin[tiab] OR CBDCA[tiab]) OR AND AND (("randomized controlled trial"[publication Type] OR "controlled clinical trial"[publication Type] OR randomized[tiab] OR placebo[tiab] OR "clinical trials as topic"[mesh:noexp] OR randomly[tiab] OR trial[ti])) NOT ((animals[mesh] NOT (humans[mesh] AND animals[mesh]))) 519 EMBASE 1. 'ovary cancer'/de OR 'ovary adenocarcinoma'/exp OR 'ovary carcinoma'/exp OR 'ovary metastasis'/exp

39 2. Ovarian:ab,ti OR Ovary:ab,ti OR Ovaries:ab,ti OR adnexa:ab,ti OR adnexal:ab,ti 'ovary'/exp OR cancer:ab,ti OR malignant:ab,ti OR carcinoma:ab,ti OR neoplasm:ab,ti OR cancers:ab,ti OR malignancy:ab,ti OR carcinomas:ab,ti OR neoplasms:ab,ti OR Adenocarcinoma:ab,ti OR Adenocarcinomas:ab,ti 'endometrioid carcinoma'/exp OR AND OR Antineoplastic:ab,ti OR Antineoplastics:ab,ti OR 'Anti neoplastic':ab,ti OR 'Anti-neoplastic':ab,ti OR Antineoplastically:ab,tiOR Chemotherapeutic:ab,ti OR Anticancer:ab,ti OR Chemotherapy:ab,ti OR Anti-cancer:ab,ti OR 'Anti cancer':ab,ti OR Chemotheraphy:ab,ti OR Chemotherapic:ab,ti OR Chemotherapies:ab,ti OR 'Chemo therapy':ab,ti OR 'Chemo-therapy':ab,ti 'antineoplastic agent'/exp OR 'chemotherapy'/exp OR triweekly:ab,ti OR weekly:ab,ti OR 'dose dense':ab,ti AND ('paclitaxel'/exp OR paclitaxel:ab,ti OR Taxol:ab,ti) and ('carboplatin'/exp OR carboplatin:ab,ti OR CBDCA:ab,ti) OR AND 'crossover procedure'/exp OR 'double blind procedure'/exp OR 'randomized controlled trial'/exp OR 'single blind procedure'/exp OR random* OR factorial* OR crossover* OR 'cross over' OR 'cross-over' OR placebo* OR (doubl* AND blind*) OR (singl* AND blind*) OR assign* OR allocat* OR volunteer* AND NOT 'nonhuman'/de 1370 COCHRANE 1. MeSH descriptor: [Ovarian Neoplasms] this term only Ovarian OR Ovary OR Ovaries OR adnexa OR adnexal:ab,ti,kw MeSH descriptor: [Adnexa Uteri] explode all trees" MeSH descriptor: [Ovary] explode all trees cancer OR malignant OR carcinoma OR neoplasm OR cancers OR malignancy OR carcinomas OR neoplasms OR Adenocarcinoma OR Adenocarcinomas:ab,ti,kw MeSH descriptor: [Adenocarcinoma] explode all trees MeSH descriptor: [Carcinoma, Endometrioid] explode all trees or ((2 or 3 or 4) and (5 or 6 or 7)) /trail 3209 상기방법을이용하여검색하였을때, 총 1,884개의논문이검색되었다. 이논문들을아래와같은 inclusion 및 exclusion criteria를적용하여, 최종적으로 3개의논문을선정하였다. 37

40 부인암진료권고안 v.3.0 Figure 1. Flow chart of searching strategy for answering KQ 문헌평가최종선정된 3개의논문은모두 RCT 연구이었으며, 연구설계의적정성을평가하기위하여 Quality Assessment of Diagnostic Accuracy Studies (QUADAS) 을사용하였다. 3개논문의평가결과는아래표에요약하였다. Table 2. Chart shows study design characteristics 38

41 3-4. 근거수준과권고등급결정을위한내용및근거 본핵심질문에대한근거는 3개의 RCT 연구결과에의해지지되었음. OS구체적으로는 PFS 에관해서는 3개의 RCT 논문이모두이용되었으나, Pignata S, 2014 연구는 PFS 와 OS 결과가일관되지않아 OS 에관해서는 2개의 RCT 연구만이최종근거수준결정에이용됨. Quality of evidence 분석결과는 PFS와 OS 모두 moderate 였음. ( 근거수준 : MODERATE) Estimation of GRADE 3-5. 메타분석 본권고안에서는진행성상피성난소암에서 first-line dose-dense chemotherapy 가 conventional 39

42 부인암진료권고안 v.3.0 chemotherapy 에비해생존율을향상시키는지확인하기위하여메타분석을시행하였다. 그결과, 두 그룹간의생존율에유의한차이를확인하지못했다. Figure 2. Result of meta-analysis 3-6. 참고문헌 [KQ3] 1. Katsumata N, Yasuda M, Takahashi F, et al. Dose-dense paclitaxel once a week in combination with carboplatin every 3 weeks for advanced ovarian cancer: a phase 3, open-label, randomised controlled trial. Lancet. Oct ;374(9698): Pignata S, Scambia G, Katsaros D, et al. Carboplatin plus paclitaxel once a week versus every 3 weeks in patients with advanced ovarian cancer (MITO-7): a randomised, multicentre, open-label, phase 3 trial. The Lancet. Oncology. Apr 2014;15(4): van der Burg ME, Onstenk W, Boere IA, et al. Long-term results of a randomised phase III trial of weekly versus three-weekly paclitaxel/platinum induction therapy followed by standard or extended three-weekly paclitaxel/platinum in European patients with advanced epithelial ovarian cancer. European journal of cancer. Oct 2014;50(15):

43 [KQ 4] 핵심질문 질문 : 상피성난소암환자에서수술후일차 (first-line) 및재발시이차 (second-line) 치료로서 bevacizumab 이생존율을향상시키는가? [KQ 4.1] [KQ 4.2] 상피성난소암환자에서수술후일차요법으로서 bevacizumab은무진행생존율을향상시키므로, 사용할수있다. [Level 2A] ( 권고등급 2=weak; 근거수준 A=high) 재발성상피성난소암환자에서이차요법으로서 bevacizumab은무진행생존율을향상시키므로, 사용할수있다. [Level 2A] ( 권고등급 2=weak; 근거수준 A=high) 단, 백금저항성재발환자에서 bevacizumab 사용은우선적으로권고된다. [Level 1] 4-2. 문헌검색문헌검색은 Pubmed, Embase, Cochrane을이용하였으며, 검색식은아래와같다. Table 1. Procedure used for MEDLINE, EMBASE, and COCHRANE to identify eligible clinical trials for answering KQ4 MEDLINE EMBASE COCHRANE 1. "Ovarian Neoplasms"[Mesh:NoExp] Ovarian[tiab] OR Ovary[tiab] OR Ovaries[tiab] OR adnexa[tiab] OR adnexal[tiab] "adnexa uteri"[mesh] OR "Ovary"[Mesh] OR cancer[tiab] OR malignant[tiab] OR carcinoma[tiab] OR neoplasm[tiab] OR cancers[tiab] OR malignancy[tiab] OR carcinomas[tiab] OR neoplasms[tiab] OR Adenocarcinoma[tiab] OR Adenocarcinomas[tiab] ("Adenocarcinoma"[Mesh]) OR "Carcinoma, Endometrioid"[Mesh] OR AND OR "bevacizumab"[supplementary Concept] OR "bevacizumab"[tiab] OR Avastin[tiab] AND 'ovary cancer'/de OR 'ovary adenocarcinoma'/exp OR 'ovary carcinoma'/exp OR 'ovary metastasis'/exp Ovarian:ab,ti OR Ovary:ab,ti OR Ovaries:ab,ti OR adnexa:ab,ti OR adnexal:ab,ti 'ovary'/exp OR cancer:ab,ti OR malignant:ab,ti OR carcinoma:ab,ti OR neoplasm:ab,ti OR cancers:ab,ti OR malignancy:ab,ti OR carcinomas:ab,ti OR neoplasms:ab,ti OR Adenocarcinoma:ab,ti OR Adenocarcinomas:ab,ti 'endometrioid carcinoma'/exp OR AND OR 'bevacizumab'/exp OR bevacizumab:ab,ti OR avastin:ab,ti AND NOT ('editorial'/it OR 'erratum'/it OR 'letter'/it OR 'note'/it OR 'short survey'/it) NOT ('animal model'/de OR 'human cell'/de OR 'in vitro study'/de OR 'nonhuman'/de) MeSH descriptor: [Ovarian Neoplasms] this term only Ovarian OR Ovary OR Ovaries OR adnexa OR adnexal:ab,ti,kw MeSH descriptor: [Adnexa Uteri] explode all trees"

44 부인암진료권고안 v MeSH descriptor: [Ovary] explode all trees cancer OR malignant OR carcinoma OR neoplasm OR cancers OR malignancy OR carcinomas OR neoplasms OR Adenocarcinoma OR Adenocarcinomas:ab,ti,kw MeSH descriptor: [Adenocarcinoma] explode all trees MeSH descriptor: [Carcinoma, Endometrioid] explode all trees or ((2 or 3 or 4) and (5 or 6 or 7)) /trail 3209 상기방법을이용하여검색하였을때, 총 1,756개의논문이검색되었다. 이논문들을아래와같은 inclusion 및 exclusion criteria를적용하여, 최종적으로 4개의논문을선정하였다. Figure 1. Flow chart of searching strategy for answering KQ 문헌평가최종선정된 4개의논문은모두 RCT 연구이었으며, 연구설계의적정성을평가하기위하여 Quality Assessment of Diagnostic Accuracy Studies (QUADAS) 을사용하였다. 4개논문의평가결과는아래표에요약하였다. 42

45 4-4. 근거수준과권고등급결정을위한내용및근거 본핵심질문에대한근거는 4개의 RCT 연구결과에의해지지되었음 (2 first-line; 2 second-line). First-line 과 second-line 치료로서사용시모두 PFS에대해서는일관되게유의한증가결과를보여높은근거수준 (HIGH) 을갖는것으로평가되나, OS는뚜렷한차이가없어근거수준 MODERATE임. Estimation of GRADE 43

46 부인암진료권고안 v 메타분석본권고안에서는상피성난소암환자에서수술후 first-line 및재발시 second-line 치료로서 Bevacizumab이생존율을향상시킬수있는지확인하기위하여메타분석하였다. 그결과, first-line 치료로사용시 OS증가에대하여유의하나신뢰구간이길고 1로매우근접 (0.99) 하고있어효과가있다고판단하기에제한적임. 하지만, PFS는유의한증가소견을보이고있음 (HR 0.82; 95% CI ). Second-line 치료로사용시에도유사하게 PFS는유의하게증가소견을보이나 (HR 0.48; 95% CI ), OS증가에대해서는연구결과를신뢰할만한충분한사건수만큼사망이발생하지않았음 ( ). Figure 2. Result of meta-analysis for first-line treatment Figure 3. Result of meta-analysis for second-line treatment 4-6. 참고문헌 [KQ4] 1. Burger RA, Sill MW, Monk BJ, Greer BE, Sorosky JI. Phase II trial of bevacizumab in persistent or recurrent epithelial ovarian cancer or primary peritoneal cancer: a Gynecologic Oncology Group Study. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. Nov ;25(33): Perren TJ, Swart AM, Pfisterer J, et al. A phase 3 trial of bevacizumab in ovarian cancer. The New England journal of medicine. Dec ;365(26): Aghajanian C, Blank SV, Goff BA, et al. OCEANS: a randomized, double-blind, placebo-controlled phase III trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. Jun ;30(17): Pujade-Lauraine E, Hilpert F, Weber B, et al. Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: The AURELIA open-label randomized phase III trial. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. May ;32(13):

47 [KQ 5] 핵심질문 질문 : 자궁부속기종양이있는환자에서 ROMA는난소암감별진단의민감도와특이도에있어서 CA-125 보다우수한가? [KQ 5] 자궁부속기종양이있는환자에서난소암감별진단을위해 ROMA 를시행할수있다. [Level 2D] ( 권고등급 2=weak; 근거수준 D=very low) 5-2. 문헌검색문헌검색은 Pubmed, Embase, Cochrane을이용하였으며, 검색식은아래와같다. Table 1. Procedure used for MEDLINE, EMBASE, and COCHRANE to identify eligible clinical trials for answering KQ5 MEDLINE 1. "Ovarian Neoplasms"[Mesh:NoExp] Ovarian[tiab] OR Ovary[tiab] OR Ovaries[tiab] OR adnexa[tiab] OR adnexal[tiab] "adnexa uteri"[mesh] OR "Ovary"[Mesh] OR cancer[tiab]or malignant[tiab] OR carcinoma[tiab] OR neoplasm[tiab] OR cancers[tiab] OR malignancy[tiab] OR carcinomas[tiab] OR neoplasms[tiab] OR Adenocarcinoma[tiab] OR Adenocarcinomas[tiab] ("Adenocarcinoma"[Mesh]) OR "Carcinoma, Endometrioid"[Mesh] OR AND OR "Epididymal Secretory Proteins"[tiab] OR "Risk of Ovarian Malignancy Algorithm"[tiab] OR ROMA[tiab] OR HE4[tiab] OR "Human Epididymal Proteins 4"[tiab] OR "Epididymal Secretory Protein"[tiab] OR "Human Epididymal Protein 4"[tiab] OR "HE-4"[tiab] "Epididymal Secretory Proteins"[Mesh] OR AND EMBASE 1. 'ovary cancer'/de OR 'ovary adenocarcinoma'/exp OR 'ovary carcinoma'/exp OR 'ovary metastasis'/exp Ovarian:ab,ti OR Ovary:ab,ti OR Ovaries:ab,ti OR adnexa:ab,ti OR adnexal:ab,ti 'ovary'/exp OR cancer:ab,ti OR malignant:ab,ti OR carcinoma:ab,ti OR neoplasm:ab,ti OR cancers:ab,ti OR malignancy:ab,ti OR carcinomas:ab,ti OR neoplasms:ab,ti OR Adenocarcinoma:ab,ti OR Adenocarcinomas:ab,ti 'endometrioid carcinoma'/exp OR AND OR 'Epididymal Secretory Proteins':ab,ti OR 'Risk of Ovarian Malignancy Algorithm':ab,ti OR ROMA:ab,ti OR HE4:ab,ti OR 'Human Epididymal Proteins 4':ab,ti OR'Epididymal Secretory Protein':ab,ti OR 'Human Epididymal Protein 4':ab,ti OR 'HE-4':ab,ti 'epididymal secretory protein'/exp OR 'human epididymis protein 4'/exp OR AND NOT ('in vitro study'/de OR 'nonhuman'/de)

48 부인암진료권고안 v.3.0 COCHRANE 1. MeSH descriptor: [Ovarian Neoplasms] this term only Ovarian OR Ovary OR Ovaries OR adnexa OR adnexal:ab,ti,kw MeSH descriptor: [Adnexa Uteri] explode all trees" MeSH descriptor: [Ovary] explode all trees cancer OR malignant OR carcinoma OR neoplasm OR cancers OR malignancy OR carcinomas OR neoplasms OR Adenocarcinoma OR Adenocarcinomas:ab,ti,kw MeSH descriptor: [Adenocarcinoma] explode all trees MeSH descriptor: [Carcinoma, Endometrioid] explode all trees or ((2 or 3 or 4) and (5 or 6 or 7)) /trail 3209 상기방법을이용하여검색하였을때, 총 514개의논문이검색되었다. 이논문들을아래와같은 inclusion 및 exclusion criteria를적용하여, 최종적으로 2개의논문을선정하였다. Figure 1. Flow chart of searching strategy for answering KQ 문헌평가최종선정된 2개의논문은모두 NRS 연구이었으며, 연구설계의적정성을평가하기위하여 Ottawa Quality Assessment Scale을사용하였다. 2개논문의평가결과는아래표에요약하였다. 46

49 5-4. 근거수준과권고등급결정을위한내용및근거 본핵심질문에대한근거는 2개의 NRS 연구결과에의해지지되었음. 2개의연구결과모두 CA-125 에더하여 HE4 를추가하면 (ROMA), ROC곡선의 AUC 가증가하는것처럼보이나, cut-off value 없이특이도에따른민감도를제시하고있어서직접적인비교가어려움. ( 근거수준 : VERY LOW) Estimation of GRADE Figure 1. ROC curves of CA-125 alone (left) and combination of CA-125 and HE4 (ROMA) (right) 참고문헌 [KQ5] 1. Moore RG, Brown AK, Miller MC, et al. Utility of a novel serum tumor biomarker HE4 in patients with endometrioid adenocarcinoma of the uterus. Gynecologic oncology. Aug 2008;110(2): Kim YM, Whang DH, Park J, et al. Evaluation of the accuracy of serum human epididymis protein 4 in combination with CA-125 for detecting ovarian cancer: a prospective case-control study in a Korean population. Clinical chemistry and laboratory medicine : CCLM / FESCC. Mar 2011;49(3):

50 부인암진료권고안 v.3.0 [KQ 6] 핵심질문 질문 : 장액성경계성난소종양 (serous borderline ovarian tumor) 에서포괄적병기설정술 (comprehensive staging operation) 이생존율을향상시키는가? [KQ 6] 장액성경계성난소종양에서포괄적병기설정술이생존율을향상시킬수있는지에대한근거수준은현재평가하기어려워, 시행권고수준결정을유보하기로하였다. [Level E] ( 근거수준 E=no evidence or difficult to analyze) 6-2. 문헌검색문헌검색은 Pubmed, Embase, Cochrane을이용하였으며, 검색식은아래와같다. Table 1. Procedure used for MEDLINE, EMBASE, and COCHRANE to identify eligible clinical trials for answering KQ6 MEDLINE 1. "Ovarian Neoplasms"[Mesh:NoExp] Ovarian[tiab] OR Ovary[tiab] OR Ovaries[tiab] OR adnexa[tiab] OR adnexal[tiab] "adnexa uteri"[mesh] OR "Ovary"[Mesh] OR cancer[tiab] OR malignant[tiab] OR carcinoma[tiab] OR neoplasm[tiab] OR cancers[tiab] OR malignancy[tiab] OR carcinomas[tiab] OR neoplasms[tiab] OR Adenocarcinoma[tiab] OR Adenocarcinomas[tiab] OR tumours[tiab] OR Tumor[tiab] OR tumour[tiab] OR Tumors[tiab] ("Adenocarcinoma"[Mesh]) OR "Carcinoma, Endometrioid"[Mesh] OR AND OR borderline[tiab] OR "Low malignant potential"[tiab] OR "Low-malignant potential"[tiab] OR "Low grade"[tiab] OR "Low-grade"[tiab] AND staging[tiab] OR "Neoplasm Staging"[Mesh] AND EMBASE 1. ''ovary tumor'/de OR ovary cancer'/de OR 'ovary adenocarcinoma'/exp OR 'ovary carcinoma'/exp OR 'ovary metastasis'/exp Ovarian:ab,ti OR Ovary:ab,ti OR Ovaries:ab,ti OR adnexa:ab,ti OR adnexal:ab,ti 'ovary'/exp OR cancer:ab,ti OR malignant:ab,ti OR carcinoma:ab,ti OR neoplasm:ab,ti OR cancers:ab,ti OR malignancy:ab,ti OR carcinomas:ab,ti OR neoplasms:ab,ti OR Adenocarcinoma:ab,ti OR Adenocarcinomas:ab,ti OR tumours:ab,ti OR Tumor:ab,ti OR tumour:ab,ti OR Tumors:ab,ti 'endometrioid carcinoma'/exp OR AND OR borderline:ab,ti OR 'Low malignant potential':ab,ti OR 'Low-malignant potential':ab,ti OR 'Low grade':ab,ti OR 'Low-grade':ab,ti AND 'cancer staging'/exp OR staging:ab,ti

51 AND NOT ('human cell'/de OR 'nonhuman'/de) 1288 COCHRANE 1. MeSH descriptor: [Ovarian Neoplasms] this term only Ovarian OR Ovary OR Ovaries OR adnexa OR adnexal:ab,ti,kw MeSH descriptor: [Adnexa Uteri] explode all trees" MeSH descriptor: [Ovary] explode all trees cancer OR malignant OR carcinoma OR neoplasm OR cancers OR malignancy OR carcinomas OR neoplasms OR Adenocarcinoma OR Adenocarcinomas:ab,ti,kw MeSH descriptor: [Adenocarcinoma] explode all trees MeSH descriptor: [Carcinoma, Endometrioid] explode all trees or ((2 or 3 or 4) and (5 or 6 or 7)) /trail 3209 상기방법을이용하여검색하였을때, 총 1,821개의논문이검색되었다. 이논문들을아래와같은 inclusion 및 exclusion criteria를적용하여, 최종적으로 1개의논문을선정하였다. Figure 1. Flow chart of searching strategy for answering KQ 문헌평가최종선정된논문은 1개의 RCT 연구이었으며, 연구설계의적정성을평가하기위하여 Ottawa Quality Assessment Scale을사용하였다. 1개논문의평가결과는아래표에요약하였다. 49

52 부인암진료권고안 v 근거수준과권고등급결정을위한내용및근거상기 PRISMA flow 에의해선정된 1개의해당논문은핵심질문 (complete staging versus incomplete staging) 의분석자료로타당하지않았다. Complete staging의유무에따른생존율차이가아닌 individual staging procedure (i.e, omentectomy, washing cytology, peritoneal biopsy) 의유무에따른생존율의차이를분석했다. 따라서 PRISMA graph는총 2359건의레코드중에서해당핵심질문의근거가되는레코드는존재하지않는것으로수정되었고, 후속메타분석이나그레이드프로작업은불가했다. ( 근거수준 E=no evidence or difficult to analyze) 6-5. 참고문헌 [KQ6] 1. Trillsch F, Mahner S, Vettorazzi E, et al. Surgical staging and prognosis in serous borderline ovarian tumours (BOT): a subanalysis of the AGO ROBOT study. British journal of cancer. Feb ;112(4):

53 [KQ 7] 핵심질문 질문 : 향후임신을원하는젊은조기상피성난소암환자에서임신능력보존수술 (fertilitysparing surgery) 은생존율에영향을미치는가? [KQ 7] 향후임신을원하는젊은조기상피성난소암환자에서포괄적병기설정술을시행할때, 임신능력보존수술은생존율을떨어뜨리지않으므로, 시행할수있다. [Level 2D] ( 권고등급 2=weak; 근거수준 D=very low) 7-2. 문헌검색문헌검색은 Pubmed, Embase, Cochrane을이용하였으며, 검색식은아래와같다. Table 1. Procedure used for MEDLINE, EMBASE, and COCHRANE to identify eligible clinical trials for answering KQ7 MEDLINE 1. "Ovarian Neoplasms"[Mesh:NoExp] Ovarian[tiab] OR Ovary[tiab] OR Ovaries[tiab] OR adnexa[tiab] OR adnexal[tiab] "adnexa uteri"[mesh] OR "Ovary"[Mesh] OR cancer[tiab] OR malignant[tiab] OR carcinoma[tiab] OR neoplasm[tiab] OR cancers[tiab] OR malignancy[tiab] OR carcinomas[tiab] OR neoplasms[tiab] OR Adenocarcinoma[tiab] OR Adenocarcinomas[tiab] ("Adenocarcinoma"[Mesh]) OR "Carcinoma, Endometrioid"[Mesh] OR AND OR "Organ Preservation"[Mesh] OR "Fertility Preservation"[Mesh] OR preservation[tiab] OR Sparing[tiab] OR save[tiab] OR saving[tiab] OR Fertility-sparing[tiab] OR conservative[tiab] OR Fertility-preserving[tiab] OR Fertility-saving[tiab] AND EMBASE 1. 'ovary cancer'/de OR 'ovary adenocarcinoma'/exp OR 'ovary carcinoma'/exp OR 'ovary metastasis'/exp Ovarian:ab,ti OR Ovary:ab,ti OR Ovaries:ab,ti OR adnexa:ab,ti OR adnexal:ab,ti 'ovary'/exp OR cancer:ab,ti OR malignant:ab,ti OR carcinoma:ab,ti OR neoplasm:ab,ti OR cancers:ab,ti OR malignancy:ab,ti OR carcinomas:ab,ti OR neoplasms:ab,ti OR Adenocarcinoma:ab,ti OR Adenocarcinomas:ab,ti 'endometrioid carcinoma'/exp OR AND OR 'organ preservation'/de OR 'fertility preservation'/exp preservation:ab,ti OR Sparing:ab,ti OR save:ab,ti OR saving:ab,ti OR Fertility-sparing:ab,ti OR conservative:ab,ti OR Fertility-preserving:ab,ti OR Fertility-saving:ab,ti OR AND NOT ('editorial'/it OR 'erratum'/it OR 'letter'/it OR 'note'/it OR 'short survey'/it) NOT ('animal experiment'/de OR 'human cell'/de OR 'in vitro study'/de OR 'nonhuman'/de) 2967 COCHRANE 1. MeSH descriptor: [Ovarian Neoplasms] this term only Ovarian OR Ovary OR Ovaries OR adnexa OR adnexal:ab,ti,kw

54 부인암진료권고안 v MeSH descriptor: [Adnexa Uteri] explode all trees" MeSH descriptor: [Ovary] explode all trees cancer OR malignant OR carcinoma OR neoplasm OR cancers ORmalignancy OR carcinomas OR neoplasms OR Adenocarcinoma OR Adenocarcinomas:ab,ti,kw MeSH descriptor: [Adenocarcinoma] explode all trees MeSH descriptor: [Carcinoma, Endometrioid] explode all trees or ((2 or 3 or 4) and (5 or 6 or 7)) /trail 3209 상기방법을이용하여검색하였을때, 총 567개의논문이검색되었다. 이논문들을아래와같은 inclusion 및 exclusion criteria를적용하여, 최종적으로 3개의논문을선정하였다. Figure 1. Flow chart of searching strategy for answering KQ 문헌평가최종선정된 3개의논문은모두 NRS 연구이었으며, 연구설계의적정성을평가하기위하여 Ottawa Quality Assessment Scale 기법을사용하였다. 3개논문의평가결과는아래표에요약하였다. 52

55 7-4. 근거수준과권고등급결정을위한내용및근거 본핵심질문에대한근거는 3 개의 NRS 연구결과에의해지지되었음. 조기상피성난소암에서 Fertility-sparing surgery 가 radical surgery 에비해서생존율에악영향이없는지에관하여평가결과 유의성을평가할수있는필요사건수에미치지못하여정확성이부족함. ( 근거수준 : VERY LOW) Estimation of GRADE 7-5. 메타분석본권고안에서는조기상피성난소암에서 Fertility-sparing surgery 가 radical surgery 에비해서생존율에악영향이없는지확인하기위하여메타분석하였다. 그결과, 조기상피성난소암에서 Fertilitysparing surgery 가 radical surgery 에비해서생존율에차이가없는것을확인하였다. 53

56 부인암진료권고안 v.3.0 Figure 2. Result of meta-analysis 7-6. 참고문헌 [KQ7] 1. Schlaerth AC, Chi DS, Poynor EA, Barakat RR, Brown CL. Long-term survival after fertility-sparing surgery for epithelial ovarian cancer. International journal of gynecological cancer : official journal of the International Gynecological Cancer Society. Oct 2009;19(7): Kajiyama H, Shibata K, Mizuno M, et al. Fertility-sparing surgery in young women with mucinous adenocarcinoma of the ovary. Gynecologic oncology. Aug 2011;122(2): Ditto A, Martinelli F, Lorusso D, Haeusler E, Carcangiu M, Raspagliesi F. Fertility sparing surgery in early stage epithelial ovarian cancer. Journal of gynecologic oncology. Oct 2014;25(4):

57 [KQ 8] 핵심질문 질문 : BRCA- 관련난소암에서 PARP 억제제유지요법은생존율을향상시키는가? [KQ 8] BRCA-관련난소암에서, 특히 BRCA 돌연변이가있는백금민감성재발성난소암환자에서, PARP 억제제유지요법은무진행생존율을향상시키므로, 사용한다. [Level 1D] ( 권고등급 1=strong; 근거수준 D=very low) 8-2. 문헌검색문헌검색은 Pubmed, Embase, Cochrane을이용하였으며, 검색식은아래와같다. Table 1. Procedure used for MEDLINE, EMBASE, and COCHRANE to identify eligible clinical trials for answering KQ1 MEDLINE 1. "Ovarian Neoplasms"[Mesh:NoExp] Ovarian[tiab] OR Ovary[tiab] OR Ovaries[tiab] OR adnexa[tiab] OR adnexal[tiab] "adnexa uteri"[mesh] OR "Ovary"[Mesh] OR cancer[tiab] OR malignant[tiab] OR carcinoma[tiab] OR neoplasm[tiab] OR cancers[tiab] OR malignancy[tiab] OR carcinomas[tiab] OR neoplasms[tiab] OR Adenocarcinoma[tiab] OR Adenocarcinomas[tiab] ("Adenocarcinoma"[Mesh]) OR "Carcinoma, Endometrioid"[Mesh] OR AND OR "Poly(ADP-ribose) Polymerases"[Mesh] "Poly(ADP-ribose) Polymerase"[tiab] OR "Poly ADP Ribose Polymerase"[tiab] OR "Poly(ADPribose) Polymerase"[tiab] OR "Poly(ADPR) Polymerase"[tiab] OR "PARP"[tiab] OR "PARP-1"[tiab] OR "PARP-2"[tiab] OR AND EMBASE 1. 'ovary cancer'/de OR 'ovary adenocarcinoma'/exp OR 'ovary carcinoma'/exp OR 'ovary metastasis'/exp Ovarian:ab,ti OR Ovary:ab,ti OR Ovaries:ab,ti OR adnexa:ab,ti OR adnexal:ab,ti 'ovary'/exp OR cancer:ab,ti OR malignant:ab,ti OR carcinoma:ab,ti OR neoplasm:ab,ti ORcancers:ab,ti OR malignancy:ab,ti OR carcinomas:ab,ti OR neoplasms:ab,ti OR Adenocarcinoma:ab,ti OR Adenocarcinomas:ab,ti 'endometrioid carcinoma'/exp OR AND OR 'nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase'/exp 'Poly(ADP-ribose) Polymerase':ab,ti OR 'Poly ADP Ribose Polymerase':ab,ti OR 'Poly(ADPribose) Polymerase':ab,ti OR 'Poly(ADPR) Polymerase':ab,ti OR 'PARP':ab,ti OR 'PARP-1':ab,ti OR 'PARP-2':ab,ti OR

58 부인암진료권고안 v AND NOT ('conference paper'/it OR 'editorial'/it OR 'letter'/it OR 'note'/it OR 'short survey'/it) NOT ('animal cell'/de OR 'animal experiment'/de OR 'animal model'/de OR 'animal tissue'/de OR 'in vitro study'/de OR 'nonhuman'/de) 747 COCHRANE 1. MeSH descriptor: [Ovarian Neoplasms] this term only Ovarian OR Ovary OR Ovaries OR adnexa OR adnexal:ab,ti,kw MeSH descriptor: [Adnexa Uteri] explode all trees" MeSH descriptor: [Ovary] explode all trees cancer OR malignant ORcarcinoma OR neoplasm OR cancers OR malignancy OR carcinomas OR neoplasms OR Adenocarcinoma OR Adenocarcinomas:ab,ti,kw MeSH descriptor: [Adenocarcinoma] explode all trees MeSH descriptor: [Carcinoma, Endometrioid] explode all trees or ((2 or 3 or 4) and (5 or 6 or 7)) /trail 3209 상기방법을이용하여검색하였을때, 총 1,020개의논문이검색되었다. 이논문들을아래와같은 inclusion 및 exclusion criteria를적용하여, 최종적으로 4개의논문을선정하였다. Figure 1. Flow chart of searching strategy for answering KQ 문헌평가최종선정된 4개의논문은 2개의 RCT 와 2개의 NRS 연구이었으며, risk of bias 평가를위하여각각 Quality Assessment of Diagnostic Accuracy Studies (QUADAS) 와 Risk of bias for interrupted time series (ITS) studies 을사용하였다. 56

59 8-4. 근거수준과권고등급결정을위한내용및근거 57

60 부인암진료권고안 v.3.0 본핵심질문에대한근거는 2개의 RCT 연구결과 (1개의 preplanned retrospective analysis from a RCT 포함 ) 에의해지지되었음. mbrca 유무가 PARPi 효과에유의하게영향을미치는것을고려할때, PARPi 사용여부에따른두군간 mbrca 여부가차이없다는것을확인해야한다. 그런데, 너무 missing 이많다. 전향적 RCT 라고보기어렵다. Well-designed 전향적 RCT 설계를위해서는 mbrca 유무와 PARPi 사용여부 2가지에따라무작위배정을시행해야함. 아직 enroll 시점에서 mbrca stauts를모두알고이를무작위배정에이용한 RCT 보고는없고, NRS 는 single arm phase II study 로, KQ8 의근거수준은 very low 로정함. ( 근거수준 : VERY LOW) (mbrca: BRCA mutation) Estimation of GRADE 8-5. 메타분석본권고안에서는 BRCA-associated ovarian cancer 에서 PARPi maintenance therapy 가생존율을향상시킬수있는지확인하기위하여메타분석을시행하였다. 그결과, mbrca (+) 인환자에서 PARPi maintenance therapy group이 placebo group에비하여무진행생존율에대한 HR 0.19 (95% CI, ) 로두그룹간에유의한차이가있음을확인하였다. Figure 2. Result of meta-analysis 8-6. 참고문헌 [KQ8] 1. Ledermann J, Harter P, Gourley C, et al. Olaparib maintenance therapy in patients with platinum sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial. The Lancet. Oncology. Jul 2014;15(8): Oza AM, Cibula D, Benzaquen AO, et al. Olaparib combined with chemotherapy for recurrent platinum-sensitive ovarian cancer: a randomised phase 2 trial. The Lancet. Oncology. Jan 2015;16(1): Kaufman B, Shapira-Frommer R, Schmutzler RK, et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. Jan ;33(3): Coleman RL, Sill MW, Bell-McGuinn K, et al. A phase II evaluation of the potent, highly selective PARP inhibitor veliparib in the treatment of persistent or recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer in patients who carry a germline BRCA1 or BRCA2 mutation - An NRG Oncology/Gynecologic Oncology Group study. Gynecologic oncology. Jun 2015;137(3):