전이성신세포암의치료에서전이병소절제술및면역화학요법을이용한복합요법의의의 The Role of Metastasectomy and Immunochemotherapy in Multimodal Therapy for Metastatic Renal Cell Carcinoma Sang-Wohn Chon, Seung Hyun Jeon, Sung-Goo Chang From the Department of Urology, School of Medicine, Kyung Hee University, Seoul, Korea Purpose: One third of renal cell caricinoma (RCC) patients present with metastatic and 20-40% of these patients who undergo nephrectomy for clinically localized RCC will develop metastases. Eventually, the number of those patients who develop metastatic will increase to 30-50%. The aim of this study is to compare the efficacy and survival rate in relation to the time of performing metastasectomy and immnuochemotherapy. Materials and Methods: We retrospectively enrolled 12 patients who had undergone radical nephrectomy, immunochemotherapy and metastasectomy between 1998 and 2007. The patients were subdivided into two groups. Group 1 included the patients who received radical nephrectomy, metastasectomy and immunochemotherapy altogether. Group 2 included the patients who developed metachronous metastases during follow-up after radical nephrectomy and so they then underwent metastasectomy and immunochemotherapy. We compared the survival rates between the two groups. Results: The sites of initial metastasis were found to be 8 cases of lung metastasis, 2 of bone metastasis, 1 of brain metastasis and 1 of colon metastasis. The 5-year survival rate of the 5 patients from group 1 was 37.5%. In group 2, the 5-year survival rate of the 7 patients was 71.4% and the -free mean interval between primary resection of the kidney and metastasectomy was 36.43±7.62 months. Statistically, there was no significant difference of survival rates between the two groups. Conclusions: The results of this study suggest that metastasectomy followed by radical nephrectomy results in a longer survival time for the patients with metastatic cancer than that of patient that undergo radical nephretomy, metastasectomy and immunotherapy at the same time. We can recommend metastasetomy any time for the RCC patients who have technical resectable metastases with possibly positive prognostic factors and a good functional condition. (Korean J Urol 2008;49:1-6) Key Words: Renal cell carcinoma, Metastasis, Immunotherapy 대한비뇨기과학회지제 49 권제 1 호 2008 경희대학교의과대학비뇨기과학교실 전상원ㆍ전승현ㆍ장성구 접수일자 :2007년 9월 21일채택일자 :2007년 11월 30일 교신저자 : 장성구경희대학교의과대학부속병원비뇨기과서울시동대문구회기동 1 번지 130-702 TEL: 02-958-8521 FAX: 02-959-6048 E-mail: sgchang@khu.ac.kr 이논문은 2007 년도정부 ( 과학기술부 ) 의재원으로한국과학재단의지원을받아수행된연구임. No R13-2002-020-02001-0 (2007). 서론신세포암은전체암의약 2% 를차지하며영상기법의발달로전세계적으로종양진단율이매년 2% 씩상승하고있 다. 조기에발견되는경우에는수술적절제로완치를기대해볼수도있으나신세포암의약 1/3은진단당시부터이미전이성암으로발견되며, 국소성암으로수술을받은경우에도약 20-40% 는추적관찰중재발을경험하게된다. 1 이와같이신세포암의 30-50% 는결국에는전이성암으로진 1
2 대한비뇨기과학회지 : 제 49 권제 1 호 2008 행하게되는데, 일단전이성으로진행하게되면예후가좋지않아생존기간은약 6-10개월에불과하며 2년생존율도 10-20% 밖에되지않는다. 2 신세포암은일반적으로항암제나방사선치료에잘반응하지않으므로이와같은전이성의경우에는치료법의선택에한계가있다. 면역치료가개발되기전에는전이성신세포암환자에서신절제술을시행하는것이환자의생존을연장시키는데아무런이점이없다는보고로인하여일부증상완화를목적으로만시행되었다. 하지만비록제한적이기는하지만면역요법에반응이있는경우잔존암을모두제거함으로써전이가발견되기까지의기간을증가시킬수도있음을보고하고있으며전이성신세포암환자에서면역요법과병행한수술요법의적용에대하여새로운기대속에많은임상연구가진행되고있으며 the Southwest Oncology Group (SWOG) trial 89498와 the European Organization for the Research and Treatment of Cancer-Genitourinary (EORTC) trial 309479의임상연구결과는전이성신세포암에서면역요법을시행하기전에종양의총량을줄이기위한종양감량신적출술 (cytoreductive nephrectomy) 을시행함으로써생존율을향상시킬수있다는가능성을증명하였다. 따라서국소적으로진행되었거나원격전이된신세포암의치료에는근치적신절제술을포함하여적극적인보조요법의적용이요구된다. 저자들은전이성신세포암환자를대상으로근치적신절제술과병행하여전이병소절제술과면역화학요법의실행시기에따른치료효과및생존율을알아봄으로써전이성신세포암에서전이병소절제술및면역화학요법의의의를찾아보고자한다. 대상및방법신세포암으로본원에서 1998년 6월부터 2007년 6월까지근치적신절제술및전이병소절제술, 면역화학요법을시행받은환자들을대상으로의무기록지를후향적으로분석하였다. 추적관찰이이루어지지않았던환자들은전화또는우편으로생존여부를확인하였고, 생존관찰기간은근치적신절제술후부터사망까지, 또는 2007년 6월관찰종료시점까지로하였다. 수술전면역화학요법을실시한경우와근치적신절제술이외에신동맥색전술등을실시한경우는본연구에서제외하였다. 모든환자들에대해원발신세포암에대해근치적신절제술을시행하였고술후종양의병기는 2002년 American Joint Committee on Cancer에따라 TNM 등급으로분류하였으며, 3 핵분화도는 Fuhrman 분류법에따라 4등급으로분류 하였다. 4 술후추적관찰은첫 3년동안은 3개월마다혈액검사와요검사, 단순흉부촬영을시행하였고 6개월마다복부전산화단층촬영을시행하였다. 두통, 반신마비등의뇌전이증상이있는경우와요통, 관절통등의골전이증상이있는경우에는증상에따라뇌전산화단층촬영과골주사검사를시행하였다. 최초진단당시에동시성원격전이가관찰되어근치적신절제술, 전이병소절제술및면역화학요법을함께시행한 5명의환자들을 1군으로분류하였고, 처음에는국소적신세포암진단하에근치적신절제술을하였으나추적관찰중전이가발견되어전이병소절제술및면역화학요법을실시한 7명의환자들은 2군으로분류하였다. 전이병소절제술은대상환자모두에서 Karnofsky performance score가 80% 이상이고단일혹은다발성전이병소의완전절제가가능한환자에서시행하였다. 면역화학요법은 1군에서는모두근치적신절제술및전이병소절제술후시행되었으며 2군에서는근치적신절제술후추적관찰중전이가발견되어전이병소절제술후면역화학요법을시행하였다. 면역화학요법은인터류킨-2, 알파인터페론, 5-fluorouracil (5-FU), 13-cis-retinoic acid (CRA), H 2-blocker를미리계획된스케줄에맞추어 8주동안투여하였다. 인터류킨-2는 1주째와 4주째에는체표면적당 2천만단위를주 3회피하주사하였고, 2주와 3주에는체표면적당 5백만단위를주 3회피하주사하였다. 알파인터페론은첫 4주간은체표면적당 6백만단위그이후 4주간은 9백만단위를주 3회투여하였다. 5-FU는 5주째부터 4주간주 1회체표면적당 750mg을정맥주사하였고 CRA는 1일 1mg/kg, H 2 blocker는 cimetidine 1회 200mg 1일 2회의용량으로경구투여하였다. 통계학적인분석방법에서 1군과 2군의종양의크기및환자의나이는 Student's t-test를이용하여유의성을비교하였다. 생존율비교는 2군에서근치적신절제술을시행한시점과전이병소절제술을시행받은시점, 두경우로구분하여각각의시점으로부터의생존기간을 1군의생존기간과비교하였다. Kaplan-Meier 생존곡선을이용하여생존에영향을미치는인자들에대한단변량분석을하였으며, log rank test로각군사이의유의성을검증하였고, p값이 0.05 미만인경우를통계학적으로차이가있다고판정하였다. 결과총 12명의환자가근치적신절제술, 전이병소절제술, 면역화학요법의병합요법을받았으며추적평균관찰기간은
전상원외 : 전이성신세포암의치료에서전이병소절제술및면역화학요법을이용한복합요법의의의 3 Table 1. Characteristics of the patients Characteristics Group 1 Group 2 (n=5) (n=7) Age (mean±se, years)* 57.00±5.40 51.86±2.58 Sex Male 4 4 Female 1 3 Mode of presentation Incidental 2 1 Symptomatic 3 6 *: p=0.030, Student's t-test, SE: Standard Error, : the patients who received radical nephrectomy, metastasectomy, and immunochemotherapy altogether. : the patients who received radical nephrectomy followed by metastasectomy and immunochemotherapy Table 2. Pathologic findings of the primary tumor (radical nephrectomy) Group 1 Group 2 p-value* Size (mean±se, cm) 9.30±2.20 6.36±0.85 0.206 Histologic type Conventional 4 5 Chromophilic 0 0 Chromophobic 1 1 Collecting duct 0 1 Initial stage T1 0 3 T2 2 1 T3 2 3 T4 1 0 Fuhrman nuclear grade Grade 2 1 1 Grade 3 3 4 Grade 4 1 2 *: Student's t-test, : sarcomatoid variants 50.42±9.82개월이었고 6명이추적관찰중사망하였다. 1군과 2군의환자수는각각 5명, 7명이었고성별은두군모두남성이각각 4명이었으며여성이 1명, 3명이었다. 환자들의평균나이는 57.00±5.40세, 51.86±2.58세였다. 최초내원시증상이없었던경우는제1군이 2례, 제2군이 1례였고증상이있었던경우는각각 3례, 6례였다 (Table 1). 근치적신절제술시종양의크기는 1군과 2군이각각 9.30±2.20cm, 6.36±0.85cm로통계적으로의미있는차이를보이지않았다 (p=0.206). 병리학적검사에서세포유형은 conventional type의경우 1군에서 4례, 2군에서 5례였고, chromophobe type은각각 1례, collecting duct type은 2군에서 1례였다. 병기는 T병기에서 T1은 2군에서 3례였고 T2는 1 Table 3. The survival rate and progression free interval according to time of metastatectomy Group 1 Group 2 p-value* 5-year survival Since radical nephrectomy 37.5% 71.4% 0.447 Since metastatectomy 37.5% 25.7% 0.704 Progression free interval (months) 36.43±7.62 *: log rank test 군에서 2례, 2군에서 1례였다. T3는 1군에서 2례, 2군에서 3례였으며 T4는 1군에서 1례였다. N병기에서는 N0가 1군에서는 4례, 2군에서는 7례였고, N1이 1군에서는 1례, 2군에서는 2례였다. 핵분화도는 Furhman Grade 3가각각 3례, 4례로가장많았다 (Table 2). 2군에서근치적신절제술시행후원격전이가발견되기까지의기간은평균 36.43±7.62개월이었다 (Table 3). 최초전이부위는폐전이가두군모두각 4례로가장많았으며이에대해쐐기절제술 5례, 폐엽절제술 2례, 폐구역절제술 1례를각각시행후면역화학요법을하였다. 이중 2례에서는전이병소가여러곳에서관찰되어전이병소를완전히절제하지못하였다. 1군, 2군에서각 2명은재발을의심할만한소견이관찰되지않았고 1명은생존해있으며 1명은신세포암의진행으로치료후 5개월만에사망하였다. 뇌전이는 1군에서 1례가관찰되었으며이에대해감마나이프및면역화학요법시행후추적관찰중골전이및폐전이로술후 49개월에사망하였다. 골전이는 2군에서 2례가관찰되었으며각각척추후궁절제술과척추골절단술및면역화학요법을시행하였고 2명모두술후각각 28개월에뇌전이및 5개월에폐전이가발생하여사망하였다. 대장전이는 2 군에서 1례가있었으며우측결장반절제술및면역화학요법을시행하였다 (Table 4). 본연구에포함된총환자들의 5년생존율은 60.5% 였으며전이병소절제술및면역화학요법시기에따라비교하였을때제1군에서 5년생존율은 37.5% 였고 2군에서근치적신절제술을시행한시점부터비교한경우 5년생존율은 71.4% 였으나 (Table 3) 통계적으로유의한차이를보이지않았다 (p=0.447, Fig. 1). 2군을전이병소절제술을시행한시점부터비교한경우 5년생존율은 25.7% 였으며 (Table 3) 역시 1군과생존율에서통계적으로유의한차이를보이지않았다 (p= 0.704, Fig. 2). 고 1939 년에 Barney 와 Churchill 5 이단일병소의폐전이를동 찰
4 대한비뇨기과학회지 : 제 49 권제 1 호 2008 Table 4. Characteristics of the patients undergoing metastasectomy Time of Site of Metastasectomy No CR Relapse PFI OS Status metastasis metastasis (No.) (Approach) 1 Synchronous Lung (1) Lobectomy CR 57 57 NED (Thoracotomy, right) 2 Synchronous Lung (2) Wedge resection CR 4 4 NED (Thoracotomy, left) 3 Synchronous Lung (1) Wedge resection CR Adrenal gland 20 43 Alive with (Thoracotomy right) 4 Synchronous Lung (1) Wedge resection IR Bone (C-spine) 3 5 Died with (Thoracotomy right) 5 Synchronous Brain Gamma knife CR Bone (T-Spine) 20 49 Died with 6 Metachronous Lung (1) Wedge resection CR 56 92 NED (Thoracotomy right) 7 Metachronous Lung (1) Segmentectomy CR 19 90 NED (Thoracotomy) 8 Metachronous Lung (3) Wedge resections CR Lung 37 43 Alive with (Thoracotomy, both) 9 Metachronous Bone Spondylectomy (L2) CR Brain 54 85 Died with 10 Metachronous Colon Hemicolectomy CR Bone 59 115 Died with 11 Metachronous Bone Laminectomy CR Lung 18 25 Died with 12 Metachronous Lung (1) Lobectomy IR Pleural 12 16 Died with (Thoracotomy, left) PFS: progression free interval, OS: overall survival, NED: no evidence of, CR: complete resection, IR: incomplete resection Fig. 1. Comparison of the cumulative survival. The survival rate of group 2 was calculated from the time of radical nephrectomy. There was no significant difference in the survival rates of the 2 groups (p=0.447 by Kaplan Meier analysis and the log rank test). Fig. 2. Comparison of the cumulative survival. The survival rate of group 2 was calculated from the time of metastasectomy. There was no significant difference in the survival rates of the 2 groups (p=0.704, by Kaplan Meier analysis and the log rank test). 반한신세포암환자에게신절제술과전이병소절제술을시행하고 23년의생존을보고한이후전이성신세포암에서전이병소절제술에관한여러임상적연구가이루어져왔다. 전이성신세포암에서전이병소의경우하나또는여러부위의전이병소를완전히제거할수있다면 30% 이상에서장기간의생존율향상을기대할수있으나, 6,7 그결과는
전상원외 : 전이성신세포암의치료에서전이병소절제술및면역화학요법을이용한복합요법의의의 5 전이부위의위치에따라매우다양하다. 폐로전이된경우가예후가좋은것으로알려져있으므로신세포암으로인한폐전이는완전히절제할수있다면장기간의생존율증가를기대할수있으므로수술적제거술을적극적으로고려해야한다. 8 전이성신세포암에서면역화학요법과수술의병합치료에관하여많은보고가있으나각각의치료의시기에관하여많은논란이있다. Flanigan 등 9 은종양감량수술과 INFα 면역요법을병행하는경우생존기간을연장시키는것으로보고하였으나 Bennett 등 10 은 30명의전이성신세포암환자에서신절제술을시행한결과 77% 의환자에서병이진행되거나수술과관련된유병률및사망률증가로추가적인면역요법을시행하지못하였고 Fallick 등 11 도면역요법을위한수술적치료는선택된환자에서만시행해야한다고주장하였다. 하지만대부분의경우에수술후합병증의위험도가낮으며, 합병증으로인하여면역요법을시행하지못한경우도 30% 미만이었으며실제로저자들의경우에도수술의합병증으로인해면역요법을시행하지못한경우는없었다. 면역요법이 15-38% 10,12 의반응률을보인다고보고되었지만면역요법만으로는완전관해를보이는경우가극히드물고 Sella 등 13 의보고와같이전이병소의수술전에면역치료를시행한환자중다수의환자 (88%) 에서전이병소에암세포가남아있기때문에여전히면역요법과전이병소절제술의병합치료는전이성신세포암에서중요한치료방법으로고려되고있다. 전이성신세포암에서전이병소의절제술이후생존율에영향을미치는가장중요한예후인자는전이병소의완전절제이다. Cerfolio 등 14 은단일병소와다발성병소를포함한폐전이신세포암환자에서완전절제시 35.9% 의 5년생존율을보고하였고, Kavolius 등 7 은폐, 뇌, 골, 피하조직, 선조직에전이가있는 141명의신세포암환자에서불완전절제시 14% 의 5년생존율을보인반면, 완전절제시 44% 의 5년생존율을보고하였다. 저자들의경우에도불완전절제가이루어졌던 2례에서는추가적인면역화학요법에도불구하고모두술후 4개월후사망하였다. 이시성원격전이와동시성원격전이가전이병소절제술이후생존율에영향을미치는가에대하여 O'dea 등 15 은동시성원격전이환자보다이시성원격전이환자에서전이병소절제술이후더좋은생존율을보고하였으나, Dreicer 등 16 은전이병소절제술이후생존율의의미있는차이가없음을보고하였다. 본연구에서도비록통계적으로생존율의의미있는차이가없었지만 5년생존율이동시성원격전이환자에서 37.5%, 이시성원격전이환자에서 71.4% 로큰차이를보였다. 술전면역화학요법이전이병소절제술이후생존율에영향을미치는지에대하여 Krishnamurthi 등 17 은생물학적반응조절물질을먼저시행함으로써좀더좋은예후를보이는특성을가진암을선택할수있기때문에생물학적반응조절물질치료에객관적반응을보이는제한된환자에서전이병소절제술을시행하여야생존율을향상시킬수있다고하였다. 하지만 Tanguay 등 18 은면역치료를시행하고객관적반응을보인환자에서전이병소절제술을시행한군과수술적치료를먼저시행한군에서생존율의차이를확인하지못했다고하였다. 본연구의경우수술적절제가가능한전이병소인경우적극적인수술적치료및면역화학요법을시도한결과 5년생존율이 60.4% 로다른전이병소절제술에관한연구결과보다장기간의생존결과를보였다. 따라서면역화학요법을포함한전신적치료와함께, 가능한수술요법을적극적으로시행한다면전이성신세포암환자들에서도보다좋은예후를기대할수있을것으로생각한다. 본연구에서증례가적기때문에전이성신세포암환자에서전이발생시기에상관없이전이병소절제술과추가적인면역화학요법이생존율을증가시키는데효과적이라고결론을맺을수는없지만충분한가능성은예시하고있다고생각한다. 결 전이성신세포암으로전이병소절제술및면역화학요법을시행한환자에서 5년생존율이 60.4% 였으며전이성신세포암에대해전이병소의절제및면역화학요법시기에따른두군의생존율및전이가발견되기까지의기간이유의한차이를보이지않았다. 전이성신세포암에서환자의전신상태가수술에적합하다면전이의발생시기에상관없이전이병소절제술과추가적인면역요법을시행하는것이환자의생존율을증가시킬수있는효과적인치료방법이라고생각한다. 론 REFERENCES 1. Motzer RJ, Russo P. Systemic therapy for renal cell carcinoma. J Urol 2000;163:408-17 2. Figlin RA, Pierce WC, Kaboo R, Tso CL, Moldawer N, Gitlitz B, et al. Treatment of metastatic renal cell carcinoma with nephrectomy, interleukin-2 and cytokine-primed or CD8 (+) selected tumor infiltrating lymphocytes from primary tumor. J Urol 1997;158:740-5 3. Greene FL, Page DL, Fleming ID, Fritz A, Balch CM, Haller
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