대한내과학회지 : 제 77 권제 6 호 2009 종설 (Review) 췌장암의최신치료 연세대학교원주의과대학내과학교실소화기내과 김재우 Recent treatment of pancreatic cancer Jae Woo Kim, M.D. Division of Gastroenterology and Hepatology, Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea Pancreatic cancer has a high mortality rate and short survival as a result of the high incidence of metastatic disease at diagnosis, the fatal clinical course, and the lack of successful therapeutic strategies. Gemcitabine remains the only standard of care for this disease. Increasing combination therapies containing gemcitabine have been tested or are undergoing investigation. In the last decade, despite a number of clinical trials assessing novel cytotoxic agents and cell signaling inhibitors, the overall survival has reached a plateau that remains difficult to improve on. This review presents recent developments involving newer chemotherapeutic and molecular targeted agents, and identifies efforts for individualized treatment strategies. (Korean J Med 77:695-702, 2009) Key Words: Pancreatic cancer; Gemcitabine; Survival; Clinical trial 서론췌장암은 5년생존율이 5% 이하로알려진예후가안좋은암이다. 대부분이진행된병기에발견되어수술적절제가가능한경우는 20% 이내이고, 절제를하여도미세전이및림프절재발이많다. 수술적절제가불가능한환자에게필요한항암화학요법및방사선치료도생존율향상과증상개선측면에서발전되고있으나아직장기생존율에서는큰변화가없는상태이다. 따라서장기생존을기대할수있는유일한방법은조기발견하여근치적절제술을시행하는것이다 1,2). 췌장암은나라에따라발생률에차이가있으나소화기암중발생률대비사망률이가장높은암으로알려져있다. 암사망원인으로서구에서는 4위를차지하고국내에서는 6위를 차지하는악성종양으로비록췌장암이모든암환자의 2~3% 에해당하지만모든암사망률의 6% 을차지한다 3). 췌장암의불량한예후는생물학적특성과수술적절제가어려운데그원인이있다. 근치적절제술을시행한경우에도재발률이높아 5년생존율은 20% 에미치지못한다. 환자를치료하는병원과외과의의적극성에따라절제여부가달라지기도하나, 영상소견에서절제가가능하여근치적수술을시행한경우에도수술후 2~3개월이내에다발성의간전이가발견되는예가많고임상적으로발견이되지않는간전이도빈번하여치료에어려움이있다. 본종설은현재시점에서적용될수있는수술적절제후의보조항암요법, 진행성암에서의항암치료및표적치료의효과, 일차항암제내성환자에서의 2차약제사용에중점을두면서기술하기로하겠다. - 695 -
- The Korean Journal of Medicine: Vol. 77, No. 6, 2009 - 수술적절제여부에따른병기분류원격전이가없는국소진행된췌장암은해부학적위치가비교적절제가용이한위치에있어근치적절제 (R0 resection) 가가능하다고생각되는군 (resectable pancreatic cancer) 과근치적절제가불가능하다고생각되는군 (unresectable pancreatic cancer) 으로나누고있으며, 이둘의중간에근치적절제가가능할수도있다고여겨지는군 (borderline resectable pancreatic cancer) 을분류하기도한다 ( 표 1) 4,5). 현재전체췌장암환자의 5~25% 만이진단당시수술적절제가가능하며이경우 13~20개월의중앙생존기간을보인다. 많은환자들은진단시전이가존재하며생존기간이 3~6개월정도로매우나쁜예후를보인다. 그리고전이성병변이없이국소적으로국한된암병변을보이나수술적인절제가불가능한경우를국소진행성췌장암 (locally advanced pancreatic cancer) 이라하며전이성 (metastatic) 췌장암과통틀어진행성췌장암으로정의한다. 수술후보조항암치료요법 GITSG (Gastrointestinal Tumor Study Group) 의연구에서수술후에방사선치료와 5-FU 병합치료를받고이어서 5-FU로유지화학요법을받은군에서유의하게생존기간 (20 개월대 11개월 ) 이향상되는것으로보고되었으나 6), 적은환자수, 조기종료, 적정량이하의방사선요법을받은환자를포함하고있다는단점을가진다. 또한, EORTC (European Organization for Research and Treatment of Cancer) 가시행한연구에서도 5-FU와방사선치료를병행한군에서생존기간 (24.5개월대 19개월 ) 이더길었으나통계적으로유의하지는않았다 7). 그러나이연구도방사선분획치료와적정량이하의방사선투여라는취약함을가지고있다. ESPAC (European Study Group for Pancreatic Cancer)-1 연구의경우 5-FU와 leucovorin을투여한항암치료군에서대조군보다전체생존율 (20.1개월대 15.5개월, p=0.009) 의향상을보였으나, 항암화학방사선치료를시행한군에서는오히려대조군보다전체생존율 (15.9개월대 17.9개월, p=0.05) 이나쁜결과를보였다 8). 그러나이연구도방사선치료주입량의적정량문제등의논란의여지가있다. CONKO-1 연구에서는췌장암수술후에 gemcitabine을 6달동안투여한군에서대조군에비해통계적으로유의한무병생존기간 (disease free survival) 의연장을보였다 (13.4개월대 6.9개월, p<0.001). 그러나양군간에전체생존기간 (overall survival) 에는유의한차이가없었다 (22.1개월대 20.2개월, p=0.06) 9). RTOG (Radiation Therapy Oncology Group) 9704 연구에서는췌장암수술을받은 442명의환자를대상으로 5-FU 근간항암화학방사선치료전후에 gemcitabine 치료를받은군과 5-FU 치료를받은군을비교하였을때, 전체비교에서는유의한차이가없었으나, 췌장두부암환자만따로분석할경우에는 gemcitabine 투여군의치료성적이 5-FU 투여군 ( 중앙생존기간, 20.5개월대 16.9개월 ) 보다우수하였다 10). 2009년에발표된 ESPAC-3 연구에서는췌장암수술 8주전부터투여를시작하여 6달동안추적한후에 5-FU, leucovorin 병합 Table 1. Anderson criteria for the resectability of pancreatic cancer Vessel Resectable Borderline resectable Locally advanced Superior mesenteric artery (SMA) Celiac axis/hepatic artery Superior mesenteric vein/portal vein No extension; normal fat plane between the tumor and the artery No extension Patent Tumor abutment 180 (one half or less) of the circumference of the artery; peri arterial stranding and tumor points of contact forming a convexity against the vessel improve chances of resection Short segment encasement/abutment of the common hepatic artery (typically at the gastroduodenal origin); the surgeon should be prepared for vascular resection/ interposition grafting Short segment occlusion with suitable vessels above and below; segmental venous occlusion alone without SMA involvement is rare and should be apparent on computed tomography - 696 - Encased (> 180 ) Encased and no technical option for reconstruction usually because of extension to the celiac axis/splenic/left gastric junction or the celiac origin Occluded and no technical option for reconstruction From Varadhachary GR, Tamm EP, Abbruzzese JL, et al. Borderline resectable pancreatic cancer: definitions, management, and role of preoperative therapy. Ann Surg Oncol 13:1035 1046, 2006
- Jae Woo Kim. Recent treatment of pancreatic cancer - 투여군과 gemcitabine 투여군을비교하였을때전체생존율 (23.0개월대 23.6개월, p=0.39) 에차이가없음을보였다. 이연구는 gemcitabine이 5-FU보다우수하지는못했으나안정성면에서는우월하다는점을보여주었다 10). 국소진행성췌장암에서항암화학방사선치료법 1969년에 Moertel 등이방사선단독치료에비해 5-FU 투여를병행할경우생존기간이연장된다 (6.3개월대 10.4개월 ) 고보고하였다 11). 또한, GITSG (The Gastrointestinal Tumor Study Group, 1981) 의연구에서방사선단독군 (60 Gy) 의중앙생존기간 5.3개월에비해 5-FU를병용한두군 (40 Gy+ 5-FU, 60 Gy+5FU) 에서생존기간이각각 8.4개월및 11.4개월로유의하게늘어나는것으로보고하였다 12). 이두연구결과가항암화학방사선치료의근간이되었으나, 이후 5-FU와 mitomycin을병용투여하였을때의효과를평가한 ECOG (The Eastern Cooperative Oncology Group, 2005) 연구에서는항암제의병행투여가생존기간의연장을가져오지못하는것으로나타나기도하였다 13). 최근방사선치료에사용하는항암제로 5-FU의지속주입, 경구 fluoropyrimidine 제제, gemcitabine, paclitaxel 등을사용하는연구가이루어졌으나아직표준적인항암제- 방사선요법의프로토콜은정해져있지않다. 그러나 gemcitabine은암세포의방사선에대한감수성을높이는약제로잘알려져있으며, E4201 연구는 gemicitabine 단독요법에비해방사선치료를병행한군이전체생존율 (6.7개월대 11.0개월, p= 0.034) 과 24개월생존율 (4% 대 12%) 의향상을보여주었다 14). 국소진행성췌장암치료에서항암화학방사선요법의사용은상대적으로적은환자수를대상으로시행한임상시험이기때문에일괄적으로적용하기어렵고비록보존적요법이나방사선요법단독보다는치료효과가높으나 gemcitabine 을이용한항암치료단독요법과는비슷한결과를가지면서부작용이심한편이다. 그러나항암화학방사선요법전에항암치료를먼저시행했을때는국소진행성췌장암의생존율을향상시키는것으로알려져있어전향적연구결과가기다려진다 15). 경계성절제가능성을가진국소진행성췌장암의항암치료 Berlin 등 16) 이고용량 gemcitabine 을이용한항암방사선요 법을시행하였을때, 9명의경계성절제가능성있는군중세명이수술이가능하였고, 근치적절제불가능 (unresectable) 그룹에서는 14명중한명이가능하여, 각각 1년생존율이 76%, 47% 였다고보고하였다. 또한, 2009년 ASCO에서 Chaudhary 등이 32명의국소진행성환자를대상으로 gemcitabine, oxaliplatin, cetuximab 을이용하여매 2주마다 6주기를투여한후재평가하여수술을시행하였을때절제율을 28% 로보고하였다 3). 이연구에서보여주는것처럼국소진행성췌장암의경우수술전 (neoadjuvant) 항암요법시행후에도그절제가능성은별로달라지지않았으나경계성절제가능군의경우에는더나은결과가기대된다. 따라서경계성절제가능군에대한수술전항암요법의사용을고려할수있다. 진행성췌장암의항암치료요법 1. Gemcitabine 단독요법 1997년 Burris 등이진행성췌장암에서 5-FU 투여군과 gemcitabine 투여군의효과를비교한 3상연구에서각각 4.8% 와 23.8% 의 clinical benefit response, 4.41개월과 5.65개월의중앙생존기간및 2% 와 18% 의일년생존율을보고한후 gemcitabine은국소진행성및전이성췌장암의표준치료로자리잡고있다 17). 투여방법은 7주간에걸쳐매주 1,000 mg/m 2 를 30 분에걸쳐정맥주사하고, 1주휴약한이후매 4주마다 1주간격으로 3회정맥주사하거나, 처음부터매 4주마다 1주간격으로 3회정맥주사하고 1주쉬는방법을보편적으로사용한다. Gemcitabine의항암작용을높이기위해 gemcitabine을 10 mg/m 2 /min의속도로일정하게 (fixed dose rate; FDR) 주입할때세포내의인산화된 gemcitabine 농도가최고로높아져서통상의 30분주입시보다반응률및생존기간의향상을보인다는결과도있으나 18), 부작용의빈도가증가한다는점이문제점이다. Gemcitabine이췌장암에서승인되고 12년이흐른지금시점에서도더나은성적을보이고있는항암제는없다는점은시사하는바가크다 ( 표 2). 2. Gemcitabine 과다른항암제의병용요법앞서얘기한것처럼지난 12년동안 gemcitabine에다른항암제를병행투여하여치료효과를증진시키려는시도가계속되고있다 19). Gemcitabine 단독요법과 gemcitabine과 5-FU 병용요법의효과를비교한 ECOG 연구에서는병용요법이 - 697 -
- 대한내과학회지 : 제 77 권제 6 호통권제 592 호 2009 - Table 2. Summary of the evolution of chemotherapy for advanced pancreatic cancer Pre~1996 Many drugs tested, nothing worked 1996 Gemcitabine is FDA approved 1996~2005 No drug or drug combination better than gemcitabine 2005 Gemcitabine erlotinib is FDA approved 2005 Is gemcitabine capecitabine better than gemcitabine? 2006 Gemcitabine plus oxaliplatin and fixed dose rate gemcitabine are not better than gemcitabine (30 minutes) 2006 Gemcitabine plus bevacizumab has no benefit 2007 Gemcitabine plus cetuximab has no benefit Saif MW. New developments in the treatment of pancreatic cancer. Highlights from the 44th ASCO Annual Meeting. Chicago, IL, USA. May 30~June 3, 2008. JOP. 9:391 397, 2008 유의한생존기간의증가를보이지못하였다 20). 또한, gemcitabine에 cisplatin을병용투여하였을때의효과를평가한 3 상연구에서도 cisplatin을병용투여한군에서무병생존기간 (5.3개월대 3.1개월 ) 및중앙생존기간 (7.5개월대 6.0개월 ) 의향상이있었으나통계적으로유의하지는않았다 21). 경구 5-FU제제인 capecitabine 을 gemcitabine에병용투여하였을때, capecitabine 병용군에서약간의생존기간연장 (8.4개월대 7.2개월, p=0.234) 이있었으나, 통계적으로유의하지는않았다. 다만 karnofsky performance score가 90 이상인환자를대상으로분석하였을때통계적으로유의한생존기간의연장 (10.1개월대 7.4개월, p=0.014) 이있었다 22). 표적치료제인 anti-vegf 단클론항체인 bevacizumab은 602명을대상으로한 3상연구에서생존기간의연장을보이지못하였다 ( 단독군 5.8개월대병용군 5.2개월 ). 또한 anti- EGFR 단클론항체인 cetuximab을 gemcitabine과병용할때의효과를평가한 3상연구에서병용군의중앙생존기간은 6.5 개월로, gemcitabine 단독투여군의 6개월보다약간길었지만통계적으로유의하지는않았다. 그러나 EGFR tyrosine kinase 의억제제인 erlotinib을 gemcitabine과병용투여한 3상연구에서병용투여군이단독투여군보다생존기간이통계적으로유의하게길었으며 (6.24 개월대 5.91개월, p=0.038), 1년생존율도통계적으로유의하게높았다 (23% 대 17%, p=0.023) 23). 그러나생존기간의연장효과가 0.33개월이라는점과약제의가격이높고, 부작용발생률이높다는점을고려해야한다. 최근발표된 AViTA 연구는 14) gemcitabine과 erlotinib 치료군에 bevacizumab을첨가하여투여했을때무병생존기간 (3.6개월대 4.6개월, p=0.0002) 의유의한증가는보였으나, 전체생존기간 (6.0개월대 7.1개월, p=0.2087) 은차이가없었다. 최근병합요법제제로많이사용되어지는 TS-1 (S-1) 은 1 M tegafur, 0.4 M gimeracil 및 1 M oteracil potassium으로구성된경구용 fluoropyrimidine 제제이다. 위암에서의수술후치료약제로확립되어있는상태이며췌장암에서는현재연구중이다. 5-FU 제제의항암효과를증가시키면서소화관부작용을감소시키기위해개발되어졌으며, Gemcitabine과의병합치료로사용되어진 2상연구에서무병생존기간 5.9개월, 전체생존기간 10.1개월을보고하였다 24). 2009년 ASCO (American Society of Clinical Oncology) 에서도 2편의병합요법초록이보고되어전체반응률 30.4%, 35% 를보고하였다 3). 이처럼병합요법의치료결과는단독요법에비해만족스럽지못하며, 오히려생존율을크게향상시키지못하면서환자의삶의질을떨어뜨리는경향이있음을고려해야한다. 그러나전신상태가다소양호한환자의경우에는병합요법을일차요법으로시행하더라도부작용발생이심하지않아본원에서는단독요법보다는병합요법을일차치료로사용하고있다. 3. 비 gemcitabine 단독요법 2009년 ASCO에서는전이성췌장암환자 22명에게 S-1 30 mg/m 2 을하루두번 14일투여후 7일휴식기를가지는치료를시행했을때전체생존율은 9.1개월을보였으며, 두명에서는부분관해를보고하였다. 또한, 2차약제로총 45명에게투여한 2상연구에서도전신상태가우수한 27명에서 5개월의생존율향상을보여차세대약제로서의가능성을보여주었다 3). 4. 2차 (second-line) 항암제일차약제로 gemcitabine을근간으로한단독요법내지병합요법치료를하더라도결국에는 gemcitabine에반응하지 - 698 -
- 김재우. 췌장암의최신치료 - 않으면서암이진행하는경과를대부분의환자에서관찰할수있다. 대개환자의활동도가불량하여 2차항암제치료를할수없는경우가흔하지만, 전신상태가좋은환자의경우에는 2차약제투여를고려해볼수있다. 그러나아직 2차치료에대한연구는적은상태이며확립된프로토콜은없다 25). 보통 capecitabine 등의경구용 fluoropyrimidine 제제를단독투여하거나, capecitabine 과 oxaliplatin을병용투여하기도한다. 또한, FOLFOX4 (5-FU+oxaliplatin+folinic acid) 나 FOLFIRI 3 (5-FU+folinic acid+irinotecan) 등의치료가보고되었으나추가적인연구가필요한상태이다 26,27). 최근 Gemcitabine 불응성환자를대상으로한 CONKO-3 연구는총 165명을대상으로 5-FU와 folinic acid 병합군과 5-FU, folinic acid에 oxaliplatin을추가한요법을교대로투여한군을비교하였을때무병생존기간 (13주대 9주, p=0.012), 전체생존기간 (20주대 13주, p=0.014) 의향상을교대로투여한군에서보여 2차항암제로고려해볼수있다 14). 5. 제언젬시타빈 (gemcitabine) 이처음췌장암치료에승인을받은이후로많은임상연구들이행해지고있는상황이나, 진행성췌장암에서우수한치료결과를보여주는임상시험은거의없는상태이다. 그러나비록젬시타빈보다뚜렷하게나은임상성적을보이는약제는나타나지않았으나췌장암외의암치료에서도같은상황을보였다는점을고려한다면다양한병합치료를이용한임상시험의수행은멈추어서는안된다. 보존적요법췌장암환자가호소하는통증, 체중감소, 오심, 구토, 지방변, 장관폐쇄, 담도폐쇄, 췌장기능소실, 식욕부진, 악액질, 우울증에대한보존적요법은항암치료만큼이나중요하며, 우선적으로시행해야하는치료이다 28,29). 췌장암환자에서정맥성혈전색전증의발생률은 17~57% 이며예후와연관을가진다. 최근연구는항응고제치료가항암효과뿐만아니라혈전색전증의발생도감소시켜생존율을향상시킨다고보고하였다 30). CONKO-4 연구는저분자량헤파린제제인에녹사파린의투여가전체생존율을향상시킨다고보고하였고, 총 160명의환자에게항암치료와함께에녹사파린을투여하였을때정맥혈전색전증발생률 (5% 대 14.5%) 의감소를보였다. 그러나두군간에전체생존율의차이는없었다 31). 암 환자의통증을경감시켜주고 (palliative), 병의경과중에발생할수있는증상에대한보조적인 (supportive) 돌봄은암환자를치료하는의사에게무엇보다도중요한치료라고할수있다. 내시경초음파 (EUS) 를이용한국소항암치료법 1. Interstitial brachytherapy Interstitial brachytherapy는 EUS를통하여 iodine-125 radioactive seed를삽입함으로써주위조직의괴사를유발하여암을치료하는방법이다. Siyu Sun 등이 2006년에 16명의국소진행성췌장암환자를대상으로하여 seed 삽입을시행하였고, 27% 의환자에서 partial response, 20% 에서 minimal response, 33% 에서 stable disease를보였다 32). Z. Jin 등은 22명의췌장암환자에대해 interstitial brachytherapy와항암요법을병합하였고, seed 삽입 1주일후 gemcitabine 1,000 mg/m 2, 5-FU 350 mg/m 2 /4 days를최대 6 cycle까지시행하여 9개월의중앙생존기간을보였다 33). 전반적생존율증가는없었으나통증조절에는효과적인치료법이다. 2. Onyx-015 Adenovirus처럼암치료에이용되는 replication-selective microbiological agent인 onyx-015는 E1B 55 kda gene deleted adenovirus로 p53이결여된세포에서선택적으로증식하여항암효과를나타낸다. Ian Ganly 등이 2000년에시행한 1상임상시험에서 22명의환자중다섯명의환자에서암세포의괴사를관찰하였다 34). 이후 2003년에 J Randolph Hecht 등에의해 21명의환자에대해 8주에걸쳐총 8차례주입하였으며마지막 4번은 gemcitabine 1,000 mg/m 2 을함께투여하였다. 치료후두명의 partial response, 여섯명의 stable disease, 11명의 progressive disease 결과를보고하였다 35). 3. TNFerade TNFerade 는세포고사, 암혈관억제, 면역증강을시키는 TNF-α를코딩 (coding) 하는유전자를지니고있는비복제성 adenovirus vector를이용한것이다. Chang 등은 EUS 및경피적방법 (percutaneous method) 으로국소진행췌장암에 TNFerade를주입하였고, 5-FU 를이용한항암요법및방사선치료를병행하였다 36). 전체 37명의환자중 17명은 EUS를통하여주입하였고, 20명은경피적방법으로시행하였다. 췌장암의국소조절, 무병생존기간, 전체생존기간등에유용성 - 699 -
- The Korean Journal of Medicine: Vol. 77, No. 6, 2009 - 이있음을보고하였다. 4. EUS 의유용성 췌장암은암자체의진행으로인한통증이다른어떤장기보다도심한상태이다. 비록현재까지얻어진내시경초음파를이용한암치료결과가아직임상에직접적으로적용하기는어려울지라도암통증치료에있어서 EUS의효용성은증가되어왔고직접적으로장기에근접하여치료를시행할수있다는점은향후에도기대하는바가크다고할수있다. 결 진행성췌장암환자에서전신항암치료는증상의완화및생존율향상에기여하고있다. 현재기본적인췌장암에대한항암치료는 gemcitabine 단독요법이다. 아직까지는어떤항암치료를선택하던지국소진행성췌장암의경우평균생존기간이 8~12개월, 전이성췌장암의경우 3~6개월정도이다. 췌장암의치료는지난 12년간에걸쳐 gemcitabine과수많은약제와의병합요법으로시행되어졌으나단독요법에비해이득은미미한편이다. 그러나현재도 gemcitabine이주역할을하면서두가지내지세가지약제를이용한병합요법치료가행해지고있다. 과연 gemcitabine에만의존해야되는지또는다른약제를이용한병합요법을시행해야하는것이아닌가라는의문을가지게된다. 또한, 분자생물학적발암과정의규명에따른다양한표적치료제들의등장과함께진일보하는듯보였지만그효과가탁월하지못한실정이다. 이런점때문에생물학적표적치료제및새로운세포독성치료제의개발은어느때보다도절실히필요한시점이다. 또한, 새로운약제의발견및병합요법을이용한임상시험은계속진행되어야하며 3), 심한통증과악액질등을경감시켜주기위한치료법의개발도필요하다. 론 중심단어 : 췌장암 ; 젬시타빈 ; 생존율 ; 임상시험 REFERENCES 1) Chari ST. Detecting early pancreatic cancer: problems and prospects. Semin Oncol 34:284-294, 2007 2) Ferrone CR, Brennan MF, Gonen M, Coit DG, Fong Y, Chung S, Tang L, Klimstra D, Allen P. Pancreatic adenocarcinoma: the actual 5-year survivors. J Gastrointest Surg 12:701-706, 2008 3) Li J, Saif MW. Advancements in the management of pancreatic cancer. JOP 10:109-117, 2009 4) Varadhachary GR, Tamm EP, Abbruzzese JL, Xiong HQ, Crane CH, Wang H, Lee JE, Pisters PW, Evans DB, Wolff RA. Borderline resectable pancreatic cancer: definitions, management, and role of preoperative therapy. Ann Surg Oncol 13:1035-1046, 2006 5) Katz MH, Pisters PW, Evans DB, Sun CC, Lee JE, Fleming JB, Vauthey JN, Abdalla EK, Crane CH, Wolff RA, Varadhachary GR, Hwang RF. Borderline resectable pancreatic cancer: the importance of this emerging stage of disease. J Am Coll Surg 206:833-846, 2008 6) Kalser MH, Ellenberg SS. Pancreatic cancer: adjuvant combined radiation and chemotherapy following curative resection. Arch Surg 120:899-903, 1985 7) Klinkenbijl JH, Jeekel J, Sahmoud T, van Pel R, Couvreur ML, Veenhof CH, Arnaud JP, Gonzalez DG, de Wit LT, Hennipman A, Wils J. Adjuvant radiotherapy and 5-fluorouracil after curative resection of cancer of the pancreas and periampullary region: phase III trial of the EORTC gastrointestinal tract cancer cooperative group. Ann Surg 230:776-782, 1999 8) Neoptolemos JP, Stocken DD, Friess H, Bassi C, Dunn JA, Hickey H, Beger H, Fernandez-Cruz L, Dervenis C, Lacaine F, Falconi M, Pederzoli P, Pap A, Spooner D, Kerr DJ, Buchler MW. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med 350:1200-1210, 2004 9) Oettle H, Post S, Neuhaus P, Gellert K, Langrehr J, Ridwelski K, Schramm H, Fahlke J, Zuelke C, Burkart C, Gutberlet K, Kettner E, Schmalenberg H, Weigang-Koehler K, Bechstein WO, Niedergethmann M, Schmidt-Wolf L, Roll L, Doerken B, Riess H. Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial. JAMA 297:267-277, 2007 10) Saif MW. Adjuvant treatment of pancreatic cancer in 2009: where are we?: highlights from the 45th ASCO annual meeting, Orlando, FL, USA. May 29-June 2, 2009. JOP 10:373-377, 2009 11) Moertel CG, Childs DS Jr, Reitemeier RJ, Colby MY Jr, Holbrook MA. Combined 5-fluorouracil and supervoltage radiation therapy of locally unresectable gastrointestinal cancer. Lancet 2:865-867, 1969 12) Moertel CG, Frytak S, Hahn RG, O'Connel MJ, Reitemeier RJ, Rubin J, Schutt AJ, Weiland LH, Childs DS, Holbrook MA, Lavin PT, Livstone E, Spiro H, Knowlton A, Kalser M, Barkin J, Lessner H, Mann-Kaplan R, Ramming K, Douglas HO Jr, Thomas P, Nave H, Bateman J, Lokich J, Brooks J, Chaffey J, Corson JM, Zamcheck N, Novak JW. Therapy of locally unresectable pancreatic carcinoma: a randomized comparison of high dose (6000 rads) radiation alone, moderate dose radiation (4000 rads + 5-fluorouracil), and high dose radiation + 5-fluorouracil: the Gastrointestinal Tumor Study Group. Cancer 48:1705-1710, 1981-700 -
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