대한소화기학회지 2009;54:355-363 DOI: 10.4166/kjg.2009.54.6.355 REVIEW 대장암의항암화학요법 울산대학교의과대학서울아산병원종양내과학교실 홍용상ㆍ김태원 Chemotherapy for Colorectal Cancer Yong Sang Hong, M.D. and Tae Won Kim, M.D. Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea Recent advances in chemotherapy lead to improved survival outcomes in patients with colorectal cancer. The 5-fluorouracil (5-FU) is still one of the important chemotherapeutic agents since 1950s, but the introduction of newer cytotoxic agents, irinotecan and oxaliplatin, or targeted agents, bevacizumab and cetuximab, have changed treatment strategies for these patients. A deliberate choice should be made for adjuvant chemotherapy, because it has became complicated more than ever before. Oxaliplatin plus 5-FU seemed to be superior in terms of disease-free and overall survival than 5-FU alone after curative surgery for colon cancers. However not all of these patients seemed to receive benefit from this intensive adjuvant treatment, and some limitations are present according to the postoperative stage, tumor biology and clinical characteristics. For metastatic disease, there is no doubt that more complicated strategies are present because we have more abundant chemotherapeutic agents available for metastatic setting compared to adjuvant setting. Recently, targeted agents, such as bevacizumab or cetuximab, also took an important place in the treatment of metastatic colorectal cancer, and many efforts are also made to find the biomarkers for predicting treatment responses to these targeted agents. In this review, we intended to sort up the standard strategies of chemotherapy for patients with colorectal cancer according to the latest pivotal publications. (Korean J Gastroenterol 2009;54:355-363) Key Words: Colorectal cancer; Chemotherapy; Targeted agents 대장암치료에사용되는항암제의발전 대장암의항암치료로사용되는약제중의하나인 5-fluorouracil (5-FU) 은 1950년대이후부터현재까지도많이사용되고있다. 1980년대이후 leucovorin (LV) 이도입되어 5-FU 의 modulator로써사용되고있으며 2000년대이후에는새로운세대의세포독성항암제인 irinotecan과 oxaliplatin의도입 연락처 : 김태원, 138-736, 서울시송파구풍납동아산병원길 86 울산대학교의과대학서울아산병원종양내과 Tel: (02) 3010-3910, Fax: (02) 3010-6961 E-mail: twkimmd@amc.seoul.kr * 본종설은보건복지가족부보건의료기술진흥사업의지원에의하여이루어진것임 (A062254). 으로수술후보조화학요법 (adjuvant chemotherapy) 과고식적항암화학요법 (palliative chemotherapy) 모두에서치료성적향상에기여하였다. 경구용 5-FU 제제인 capecitabine과 S-1 등이소개되어최근 5-FU의정맥주사에따르는부작용과불편함을어느정도대체해주고있으며, 2000년대중반이후에는 bevacizumab 또는 cetuximab과같은표적치료제 (targeted agent) 의도입으로전이성대장암의생존율향상에 Correspondence to: Tae Won Kim, M.D. Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, 86, Asanbyeongwon-gil, Pungnap-dong, Songpa-gu, Seoul 138-736, Korea Tel: +82-2-3010-3910, Fax: +82-2-3010-6961 E-mail: twkimmd@amc.seoul.kr
356 대한소화기학회지 : 제 54 권제 6 호, 2009 크게기여하였다. 대장암 (colorectal cancer) 은해부학적인위치에따라결장암 (colon cancer) 과직장암 (rectal cancer) 으로구분하며, 이후부터기술되는내용은, 전이성대장암 (metastatic disease) 의경우약제와용법이동일하게적용되지만, 수술치료를전제로한보조화학요법의경우결장암과직장암이구분되어이해되어야한다. 결장암의수술후보조요법 1. 5-FU/LV (FL) 수술후 2-3기의결장암 (colon cancer) 환자에서수술후보조요법 (adjuvant chemotherapy) 으로다양한용량과용법의 5-FU/LV (FL) 을사용한경우유의하게생존율이증가함이 1990년대에시행된여러무작위 3상연구에서증명되었으며, 이중현재임상에서가장많이사용되는것은 Mayo Clinic regimen (5-day bolus FL, 6개월 ) 이다. 1 2-3기의결장암환자를대상으로수술후경과관찰만한군 (151명) 과 6개월간의 FL 요법을시행한군 (158명) 을비교하였을때, 5년무재발생존율 (relapse-free survival) (58% 대 74%; p=0.001) 과 5 년전체생존율 (overall survival) 은 (63% 대 74%; p=0.02) 로모두통계적으로유의하게 FL 군에서우월함을보고하였다. 현재는 2기고위험군결장암에서는보조 FL 요법이추천될수있다. 2. Oxaliplatin/LV5FU2 (FOLFOX) Oxaliplatin은 3세대백금계항암제로, 많은소화기암에서사용되는약제이다. 2000년대이후도입되었으며, 결장암의보조화학요법에사용되고있다. LV5FU2는 de Gramont이처음도입한 5-FU/LV의지속정주용법으로 bolus 5-FU/LV (FL) 요법에비교하여효과면에서는최소한동등하며독성면에서는약간나은것으로알려져있다. MOSAIC 연구는수술후 2기와 3기의결장암에서수술후보조요법으로 LV5FU2와 FOLFOX를비교하는대규모 3상임상연구이고 1998년부터 2001년까지총 2,246명의환자가참여하였으며, 2,3 FOLFOX를시행한군에서 5년무병생존율과 6년전체생존율이통계적으로우월함을보고하였다 (Table 1). 그러나 3기에서는 FOLFOX 군의생존율향상이통계적으로우월한데반하여고위험군 2기에서는두군간의차이가관찰되지않았으며, 3기결장암이라하더라도 65세이상의고령의환자에서는 FOLFOX 가우월하지않았다는점도특이할만한점이라하겠다. 3. Capecitabine Capecitabine은경구형 fluoropyrimidine 제제로, 5-FU를사용할때따르는부작용과불편함 (5-FU 지속정주로인한입원이나중심정맥관삽입 ) 이없고효과면에서 5-FU/LV (FL 또는 LV5FU2) 과최소한동등한것으로평가되어최근적응증이늘어나고있다. 수술후 3기결장암환자를대상으로보조화학요법으로서의 Mayo Clinic regimen (FL) 과 capecitabine을비교한대규모 3상연구에따르면, 무질병생존율과전체생존율면에서동등함 (capecitabine의 non-inferiority) 이증명되었으며 (p-value for equivalence<0.001), 3도이상의호중구감소증, 구내염등의독성은 capecitabine 군에서더적었다 (p<0.001). 4 Capecitabine은 3기결장암에서보조요법으로 FOLFOX을불가피하게사용하지못하는경우에추천될수있다. 4. 그외에보조화학요법대장암에서사용되는또다른세포독성항암제로 irinotecan이있다. Irinotecan/5-FU/LV을결장암수술후보조화학요법으로시도하였던몇가지연구결과도최근발표되었으나 (CALGB 89803, PETACC-3, FFCD9802) 현재까지는 FL 요법에비해더나은성적을보고하고있지못하고있어서, 보조요법에서 irinotecan은추천되지않는다. 5-7 Anti-angiogenic agent인 bevacizumab 역시전이성대장암에서는우수한성적을보여주고있으나, 최근의발표 (NSABP-C08) 에의하면역 Table 1. Survival Outcomes in Patients with Stage II and III Colon Cancer (MOSAIC Trial) 5 year DFS 6 year OS FOLFOX LV5FU2 HR p-value FOLFOX LV5FU2 HR p-value Overall 73.3% 67.4% 0.80 0.003 78.5% 76.0% 0.84 0.046 Stage III 66.4% 58.9% 0.78 0.005 72.9% 68.7% 0.80 0.023 Stage II* 83.7% 79.9% 0.84 0.258 86.8% 86.7% 1.00 0.986 DFS, disease-free survival; OS, overall survival; HR, hazard ratio. * FOLFOX did not result in survival benefit in patients with high-risk stage II colon cancers (T4 lesion, perforated, obstructive, poorly differentiated grade of tumor, positive venous invasion, harvested less than 10 lymph nodes during surgery).
홍용상외 1 인. 대장암의항암화학요법 357 시결장암의수술후 bevacizumab/folfox 병합요법이 FOLFOX 요법에비해무진행생존기간의연장을보이지못하였다. 8 5. 직장암의보조요법 직장암의경우 2기이상 (T3 또는 N+) 에서는보조요법으로항암방사선요법이추천되며, 이는결장암의보조요법 ( 항암요법단독 ) 과는다르다. 직장암의보조항암 ( 방사선 ) 요법에서의표준약제는 5-FU/LV이며, 그용법과용량은기본적으로결장암에서의 Mayo Clinic regimen에따른다. 최근에는수술후보조항암방사선요법 (postoperative adjuvant chemoradiation) 보다수술전항암방사선요법 (preoperative chemoradiation) 이선호되며, 이는수술전항암방사선요법이국소재발률과독성면에서수술후의그것보다우월하기때문이다. 9-11 수술전항암방사선요법을시행한경우에는 4개월간의보조항암화학요법이추천된다. Capecitabine의경우최근직장암의항암방사선요법또는보조항암요법으로어느정도사용하기도하지만, 결장암과는다르게 FOLFOX가 5-FU/LV보다보조요법으로써우월하다는증거는아직없다. 6. 요약 - 보조화학요법결장암의수술후보조요법은 3기의경우무병생존율과전체생존율을향상시키는것으로알려져있는 FOLFOX가표준요법이며, 2기고위험군의경우는 FOLFOX, FL, capecitabine이고려될수있다. 현재결장암수술후보조요법으로 irinotecan과 bevacizumab은추천되지않는다. 직장암의경우는보조 FOLFOX 요법이아직증명된바가없다. 전이성대장암에서의고식적항암화학요법전이성대장암환자의생존율은최근약제의발전에따라크게향상되었으며 (Fig. 1), 표준세포독성항암제의경우 15-20개월, 표적치료제를추가하여사용한경우는 20-25개월까지중간생존기간이보고되고있다. 전이성대장암에서의고식적항암화학요법의표준은 5- FU를기본으로하는 2제병합요법으로, 5-FU에 oxaliplatin 또는 irinotecan을병합하여사용하는 FOLFOX (oxaliplatin/5- FU/LV) 또는 FOLFIRI (irinotecan/5-fu/lv) 요법이다. 12,13 이러한 2제요법이독성은비교적견딜만하면서반응률면에서는우월하기때문에 1제요법은특별한경우가아니면추천되지않는다. 세포독성항암제 3가지를모두병합하여사용하는 3제병합요법 (oxaliplatin/irinotecan/5-fu) 또한최근소개되었으나이는 2제요법에비해독성은증가하고생존율향상은미미하여 1제요법과마찬가지로일반적으로추 Fig. 1. Improvement of overall survival in patients with metastatic colorectal cancer according to the recent advances in chemotherapy. 천되지않는다. 14,15 이번종설에서는표준으로평가받고있는 2제요법과표적치료제 (bevacizumab, cetuximab) 에대해주로기술하고자한다. 1. 2 제요법 FOLFOX와 FOLFIRI 는현재전이성대장암의고식적세포독성항암요법의표준이라할수있을만큼널리인정받고있다. 각각의부작용의양상은다르지만, 반응률이나생존율측면에서는거의비슷하며두가지약제를사용하는순서에따라서도환자의전체생존율면에서는큰차이가없는것으로보고되어있다. GERCOR 연구는 2제요법의대표적인요법인 FOLFOX와 FOLFIRI 를각각순서를바꿔서사용할때의효과와부작용을알아본무작위배정연구이다. 16 A 군은 1 st line FOLFIRI 후질병이진행하면 2 nd line FOLFOX로 (FOLFIRI FOLFOX), B 군은 1 st line FOLFOX 후질병이진행하면 2 nd line FOLFIRI로 (FOLFOX FOLFIRI) 무작위배정하여치료를진행하였고, 각군에서 2 nd line treatment까지모두시행받은환자는 60-70% 가량이었다. FOLFIRI 후 FOLFOX, 또는 FOLFOX 후 FOLFIRI로무작위배정하여치료한순서에따라서는전체생존기간과 2년생존율면에서는두군간에차이를보이지않았다 (Table 2). 첫치료가 FOLFIRI인지 FOLFOX 인지에따라서도반응률은대략 50% 가량, 무진행생존기간도약 8개월정도로통계적으로차이를보이지않았다. 따라서, 약제의선택은치료에대한부작용, 표적치료제의병합, 환자의전신상태, 간질환이나말초신경병증의여부, 추후절제병소제거수술등의여러면을고려하여결정하는것이중요하다.
358 The Korean Journal of Gastroenterology: Vol. 54, No. 6, 2009 Table 2. FOLFIRI Followed by FOLFOX or the Reverse Sequence in Metastatic Colorectal Cancer, GERCOR Study Arm A (n=109) FOLFIRI FOLFOX Arm B (n=111) FOLFOX FOLFIRI p-value RR (1 st line) 56% 54% 0.68 PFS (1 st line) 8.5 mo 8.0 mo 0.26 RR (2 nd line) 15% 4% 0.05 PFS (2 nd line) 4.2 mo 2.5 mo 0.003 PFS (2 nd PD) 14.2 mo 10.9 mo 0.64 OS 21.5 mo 20.6 mo 0.99 2-year survival rate 41% 45% RR, response rate; PFS, progression-free survival; OS, overall survival. 2. 경구용 fluoropyrimidine의동등성 FOLFOX와 FOLFIRI의경우 FL의지속정주로인하여입원이필요하거나중심정맥관의확보가필요하다는점등의불편함이따르고때로는정맥혈전염, 심부정맥혈전증등의부작용이드물게발생할수있다. Capecitabine의경우 FL에비하여효과면에서는최소한동등한것이알려져있으며부작용면또는편의성면에서는 FL에비해우월한점이알려져있어서 FOLFIRI 또는 FOLFOX를 XELIRI (capecitabine +irinotecan 병합 ) 또는 XELOX (capecitabine+oxaliplatin 병합 ) 로대체하고자하는연구가많이시행되었다. XELOX의경우는 FOLFOX 와효과와부작용면에서거의동등하여, 현재전이성대장암에서 FOLFOX와 XELOX는동등한요법으로인정받고있다. 17,18 그러나, XELIRI의경우는 FOLFIRI 와비교하여효과면에서도약간열등하고부작용도조금더많은것으로알려져있어서, XELIRI 와 FOLFIRI 를비교하는대규모 3상연구가조기종료된바있다. 19,20 최근 XELIRI의변형된용법과용량 (modified XELIRI) 에대한임상연구들이진행되고있어서, 추후결과를지켜볼필요가있다. 3. 표적치료제 (targeted agents) 현재국내에서전이성대장암에사용이허가되어시판중인표적치료제는 bevacizumab (Avastin R, anti-vegf recombinant humanized monoclonal antibody) 과 cetuximab (Erbitux R, anti-egfr recombinant chimeric monoclonal antibody) 이있다. Fig. 1에서볼수있듯이, 새로운세포독성항암제 (irinotecan, oxaliplatin) 의병합만으로도전이성대장암환자의전체생존기간의중간값이약 20개월까지향상되었다. 표적치료제를병합하는경우 25개월까지생존기간이연장되었으며, 일부소규모 2상연구에의하면최장 30개월까지도보고되고있다. 현재 NCCN guideline은전이성대장암의첫치료부터표적치료제를병합하는것을추천하고있다. 이러한 표적치료제의병합은한국처럼표적치료제의보험급여가되지않는국가에서는비용-효과면에서다시고려해봐야할문제인데, 이번종설에서는이러한약물경제성측면은제외하고, 치료와적응증면만을다루기로한다. 1) Bevacizumab (Avastin R ) Bevacizumab은 circulating VEGF (vascular endothelial growth factor) 를표적으로하는 humanized IgG1 monoclonal antibody이며, 현재대장암을비롯한여러고형암종에서효과를인정받고있다. 현재까지전이성대장암에서 bevacizumab의적응증은 1차치료와 2차치료에국한되며, bevacizumab 단독으로는효과가없고세포독성항암제와병합하여사용하여야한다. Bevacizumab 은전이성대장암에서사용되는모든세포독성항암제와병합이가능하며, 어떤약제와병합하더라도효과면에서는거의동등한것으로평가되고있다. Bevacizumab 병합요법이세포독성항암제단독에비해생존기간향상됨을보고한대표적인대규모임상연구는 2004 년 Hurwitz 등 21 (irinotecan 기반요법와병합-비교 ) 과 2008년 Saltz 등 22 (oxaliplatin 기반요법과병합-비교 ) 에의해발표되었다 (Table 3). Table 3에서기술하였듯이, 첫치료로서 bevacizumab을 2 제요법에병합하여사용하는경우무진행생존기간은공통적으로연장되는것을볼수있으며, 전체생존기간의경우 bevacizumab/ifl 병합요법은 IFL에비하여통계적으로유의하게증가되었으나 bevacizumab/xelox or FOLFOX 병합요법은 XELOX or FOLFOX에비해증가하는경향만을보여주었다. Bevacizumab은 2 nd line chemotherapy와병용하여도효과적임이증명되었는데 1st line irinotecan 기반요법에진행한전이성대장암환자를대상으로 2 nd line treatment 로서 FOLFOX와 bevacizumab/folfox 를비교한 3상임상연구결과가이를뒷받침해준다 (ECOG E3200 연구 ). 23 Bevacizumab/FOLFOX를사용한군에서 FOLFOX 단독을사용
Hong YS, et al. Chemotherapy for Colorectal Cancer 359 Table 3. Pivotal Randomized Phase III Trials of Bevacizumab in Patients with Metastatic Colorectal Cancers Hurwitz et al. 21 Saltz et al. 22 IFL IFL+Bev p-value OxF OxF+Bev p-value RR 34.8% 44.8% 0.004 49% 47% 0.31 PFS (mo) 6.2 10.6 <0.001 8.0 9.4 0.0023 OS (mo) 15.6 20.3 <0.001 19.9 21.3 0.0769 RR, response rate; PFS, progression-free survival; OS, overall survival; IFL, irinotecan+bolus FL; OxF, FOLFOX or XELOX; Bev, bevacizumab. Table 4. Bevacizumab-associated Adverse Events (from the BEAT Study) Any grade Grade 3 or 4 Hypertension 30% 5% Proteinuria 10% 1% Bleeding 31% 3% Wound healing complication 4% 1% Arterial thromboembolism 2% 1% GI perforation 2% 2% 한군에비해반응률이유의하게높았으며 (22.7% vs. 8.6%, p<0.0001) 무진행생존기간역시유의하게길었다 (7.3개월 vs. 4.7개월, p<0.0001). 그러나이번연구에서사용된 2 nd line bevacizumab의용량이통상적으로 1 st line으로사용되는 5 mg/kg/2-week의두배인 10 mg/kg/2-week가사용되었다는점이한계로지적되고있다. Bevacizumab의부작용은다른세포독성항암제와는다르다. Bevacizumab 관련부작용은대규모관찰연구 (BEAT 연구 ) 의결과에서잘규명되어있으며, 이 BEAT 연구는, 1차치료약제로 bevacizumab과세포독성항암제 (FOLFOX, XELOX, FOLFIRI, fluoropyrimidine) 병합요법을총 1,965명의환자에서시행하여결과를관찰한대규모임상연구이다. 24 Bevacizumab 관련부작용은일반적인 anti-angiogenic agent가가지는부작용으로설명할수있으며 Table 4에정리하였다. 으로, cetuximab 단독과 cetuximab/irinotecan 병용요법을비교한 3상임상연구이다. 이전에 irinotecan에노출되거나표준요법에모두실패한경우에도 cetuximab/irinotecan 병용요법을시행하였을때반응률은 22.9%, 무진행생존기간은 4.1개월, 전체생존기간은 8.6개월로보고하였다. 특히 BOND trial은 cetuximab이 irinotecan에대한내성을극복할수있다는점과표준치료에모두실패한환자들에게서도추가적인종양반응률과추가생존기간연장을기대할수있다는점을보고하였다는데의의가있어중요한연구로평가받고있다. 이후 oxaliplatin 기반에실패한환자들만을대상으로 2 nd line cetuximab/irinotecan 과 irinotecan 단독을비교한 EPIC 연구, 26 1 st line treatment로써 FOLFIRI vs. cetuximab/folfiri 를비교한 CRYSTAL 연구, 27 1 st line treatment로써 FOLFOX vs. cetuximab/folfox를비교한 OPUS 연구 28 등이최근에발표되면서, 전이성대장암에서 cetuximab의 적응증을넓혀가고있다. 이러한연구들의공통점은 cetuximab이 anti-egfr monoclonal antibody이기때문에환자선택의기준을 종양조직에서 EGFR 면역염색결과가양성인경우 로제한하였다는것이다. 그러나최근의연구결과에의하면 EGFR 면역염색결과가 cetuximab의효과와연관성이없다는점이밝혀졌으며, 29,30 EGFR 신호전달체계 (signaling pathway) 에관여하는유전자중하나인 K-ras의돌연변이유무에따라서 cetuximab의효과가다르다는점이알려지면서 31,32 위의연구결과들이재해석되고있다. 2) Cetuximab (Erbitux R ) Cetuximab은세포막표면의 EGFR (epidermal growth factor receptor) 을표적으로하는 chimeric IgG1 monoclonal antibody 이다. Cetuximab 이각광받기시작된이유는, FOLFOX 나 FOLFIRI 등의표준세포독성항암요법에모두실패한경우, 특히이전에 irinotecan에노출되어실패한경우에도 cetuximab과 irinotecan을병합할때추가생존율향상이보고되었기때문이다 (BOND trial). 25 BOND trial은 irinotecan 을포함한표준세포독성항암요법에진행된환자중, 종양조직에서 EGFR 면역조직화학염색결과가양성인환자 329명을대상 3) K-ras 돌연변이여부와 cetuximab K-ras 유전자는대장암의발생에연관된여러유전자중하나로 1967년처음발견되었으며 EGFR 세포신호전달체계를구성하고있는유전자중하나이다. K-ras 돌연변이 (point mutation) 는전체대장암환자의약 40% 가량에서발견되며, 돌연변이위치는 codon 12번과 13번에서가장많고 (81%), codon 61번 (19%) 에서도일부발견된다. 33 K-ras 돌연변이여부가 cetuximab 의효과에중요한이론적인배경은 Fig. 2에서기술된바와같이, K-ras가정상 (wild-type) 인경우 EGFR을억제하는것자체가하위전달
360 대한소화기학회지 : 제 54 권제 6 호, 2009 Fig. 2. Cetuximab and K-ras modulate signaling through the epidermal growth factor receptor (EGFR) pathway. (A) Binding of ligand to EGFR triggers signaling through ras/mapk pathway to multiple targets that may regulate ligand levels. (B) In the presence of cetuximab, ligand binding is prevented, and there is deactivation of EGFR signaling in cells dependent on this pathway. (C) K-ras mutations can lead to dysregulation of MAPK pathway and downstream signaling in the absence of ligand-dependent receptor activation. Table 5. Different Efficacy Outcomes according to the K-ras Mutation Status (CRYSTAL and OPUS Trial) CRYSTAL OPUS FOLFIRI FOLFIRI+Cetuximab p-value FOLFOX FOLFOX+Cetuximab p-value Overall patients RR 38.7% 46.9% 0.004 36% 46% 0.064 PFS (mo) 8.0 8.9 0.048 7.2 7.2 OS (mo) 18.6 19.9 K-ras wild-type RR 43.2% 59.3% 0.03 37% 61% 0.011 PFS (mo) 8.7 9.9 0.07 7.2 7.7 0.0163 OS (mo) 21.0 24.9 K-ras mutant RR 40.2% 36.2% 49% 33% PFS (mo) 8.1 7.6 8.6 5.5 0.0192 OS (mo) 17.7 17.5 RR, response rate; PFS, progression-free survival; OS, overall survival. p-value: Clinically meaningful values were only recorded. 체계전체를억제하여세포증식억제의효과를보일수있지만, K-ras에돌연변이가있는경우 K-ras 아래쪽의 EGFR 신호전달체계가영구적으로활성화되어 (permanently activated) 상위단계인 EGFR을억제하여도세포증식이지속되는것을막을수없게된다는것이다 (Fig. 2). 34 이와같이, cetuximab 의효과에는 EGFR 양성여부와무관하게 K-ras 돌연변이가중요한예측인자 (predictive factor) 임이알려지면서, 이전의 3상연구들에대한결과의재해석이시도되었다. 전이성대장암환자에서 1차요법으로써의 cetuximab 의효과에대한대표적인연구인 CRYSTAL과 OPUS의결과를 K-ras 돌연변이여부에따라재해석한결과를 Table 5에정리하였다. Table 5에서보듯이, CRYSTAL 연구와 OPUS 연구모두에서, K-ras 돌연변이가 없는 경우 (wild-type) 에만 cetuximab의효과를기대할수있다. 최근이러한결과를바탕으로 cetuximab의허가사항이 K-ras 돌연변이가없는환자 에게만사용하는것으로개정되었다. 비소세포폐암의 EGFR 돌연변이와는달리, 저자들의연구에의하면대장암에서 K-ras의돌연변이의빈도는인종간의차이가없으며, 한국인에서도 K-ras 돌연변이유무에따라서 cetuximab에대한치료효과가다르다고알려져있다. 35
홍용상외 1 인. 대장암의항암화학요법 361 4) K-ras 외의다른예측인자 K-ras는 cetuximab 치료효과에대한예측인자 (negative predictive factor) 로공인을받았다. 그러나 K-ras 돌연변이가없는환자모두에게서 cetuximab이효과적인것은아니기때문에, K-ras 외에 EGFR 신호전달체계내의또다른유전자들의발현상태와 cetuximab의효과사이의연관성을규명하기위한연구들이활발하게진행되고있다. 최근 BRAF, PTEN, PI3KCA 등에 36-38 대한연구가발표되고있으나, 아직까지는추가적인연구가더필요하다. Bevacizumab의경우는아직예측인자라할만한것이없다. 일부보고에의하면조직또는혈청내의몇몇인자들과 bevacizumab 효과가연관이있다는보고는있으나 39 대부분소규모연구로아직표준으로는받아들이기는힘들다. 4. 요약 - 전이성대장암의고식적화학요법 Fluoropyrimidine+oxaliplatin 또는 irinotecan 2제요법 (FOLFOX, XELOX, FOLFIRI) 이세포독성화학요법의표준이며, oxaliplatin과 irinotecan 의노출순서에따르는전반적인효과의차이는없다. FOLFOX 와 XELOX는동등하나 XELIRI의경우 FOLFIRI 보다효능이떨어지고부작용이높을수있다는보고가있으므로주의를요한다. 처음부터 fluoropyrimidine 단독 (FL 또는 capecitabine) 을사용하는것은환자의전신상태가나쁜경우에사용될수는있으나, 그외의경우는추천되지는않는다. Bevacizumab의경우, 1 st line 또는 2 nd line 요법으로써세포독성화학요법과병행하여사용되는것이추천된다. 단, 비용-효과면에서다각적인고려가필요하며, 3 rd line 이상에서는아직명백한증거가없다. Cetuximab의경우시기와상관없이사용할수있으나, K-ras 돌연변이여부를꼭확인후 K-ras 돌연변이가없는경우에만사용하는것이허용된다. 결론최근한국인에서발병이급격히늘고있는대장암의 5년생존율은 59% (1999-2000년) 에서 66.7% (2001-2005년) 로향상되었는데, 이는 2000년대에접어들면서여러치료기술의발전이대장암환자의생존율향상에기여하였다고판단할수있다. 비단항암화학요법의발전뿐만아니라새로운수술기법, 방사선치료기법의발전, 내시경치료기법의발전또한대장암환자의생존율향상에기여하였으며, 이렇듯대장암의치료는다학제적접근을통한통합진료 (multidisciplinary team approach) 가매우중요하다. 특히대장암치료를위한항암화학요법의경우, 무조건새로운약제만을사용하는것 보다상황에따라약제의강약을적절히조절하고조합하는것이중요하다는점을기억해야한다. 최근항암화학요법의반응을예측할수있는몇몇생체표지자가발견되었고, 특히국내에서도생체표지자발견을위한연구가활발히진행중이어서이에대한결과가기대된다. 참고문헌 1. O'Connell MJ, Mailliard JA, Kahn MJ, et al. Controlled trial of fluorouracil and low-dose leucovorin given for 6 months as postoperative adjuvant therapy for colon cancer. J Clin Oncol 1997;15:246-250. 2. Andre T, Boni C, Navarro M, et al. Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J Clin Oncol 2009;27:3109-3116. 3. Andre T, Boni C, Mounedji-Boudiaf L, et al. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med 2004;350:2343-2351. 4. Twelves C, Wong A, Nowacki MP, et al. Capecitabine as adjuvant treatment for stage III colon cancer. N Engl J Med 2005;352:2696-2704. 5. Ychou M, Raoul JL, Douillard JY, et al. A phase III randomised trial of LV5FU2+irinotecan versus LV5FU2 alone in adjuvant high-risk colon cancer (FNCLCC Accord02/FFCD- 9802). Ann Oncol 2009;20:674-680. 6. Saltz LB, Niedzwiecki D, Hollis D, et al. Irinotecan fluorouracil plus leucovorin is not superior to fluorouracil plus leucovorin alone as adjuvant treatment for stage III colon cancer: results of CALGB 89803. J Clin Oncol 2007;25:3456-3461. 7. Van Cutsem E, Labianca R, Bodoky G, et al. Randomized phase III trial comparing biweekly infusional fluorouracil/ leucovorin alone or with irinotecan in the adjuvant treatment of stage III colon cancer: PETACC-3. J Clin Oncol 2009; 27:3117-3125. 8. Wolmark N, Yothers G, O'Connell MJ, et al. A phase III trial comparing mfolfox6 to mfolfox6 plus bevacizumab in stage II or III carcinoma of the colon: results of NSABP Protocol C-08. J Clin Oncol (Meeting Abstracts) 2009;27. 9. Sauer R, Becker H, Hohenberger W, et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 2004;351:1731-1740. 10. Gerard JP, Conroy T, Bonnetain F, et al. Preoperative radiotherapy with or without concurrent fluorouracil and leucovorin in T3-4 rectal cancers: results of FFCD 9203. J Clin Oncol 2006;24:4620-4625. 11. Bosset JF, Collette L, Calais G, et al. Chemotherapy with
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