KQ 9. 근치적 전립선절제술 시행시 골반림프절 절제술을 같이 시행하는 경우가 골반 림프절 절제술을 같이 시행하지 않는 경우에 비해 생존율을 높일 수 있는가?

개요

전립선암 수술에 있어 골반림프절절제술(pelvic lymph node dissection, PLND)을 시행하는 환자의 선택은 림프절전이의 가능성을 고려하여 결정되고 있다. 골반림프절전이의 가능성은 술 전 전립선특이항원(PSA) 수치, 임상병기 및 조직검사 글리슨 점수를 사용하는 노모그람을 바탕으로 예측한다[1].

그러나 중간위험 전립선암 환자에서 골반 림프절 절제술의 효용성에 있어서는 아직도 논란이 있다[2,3]. 골반 림프절 절제술은 정확한 병기의 설정 뿐만 아니라 미세 전이가 있는 일부 환자들에게 완치 기회를 제공할 수 있다는 점에서 효용이 있지만 이 자체가 수술에 따른 morbidity를 높이고 생존율에는 영 향을 미치지 않는다는 연구 결과들도 보고되고 있다[2,3].

중간위험 전립선암 환자에서 골반 림프절 절제술을 시행할 때 확대 골반 림프절 절제술을 시행함으로써 제한적 골반 림프절 절제술보다 2배 정도 전이성 병변을 더 많이 찾아 낼 수 있다[4]. 확대 골반림프절절제술의 범위는 전측면으로는 외장골정맥, 외측면으로는 외측골반벽, 내측면으로는 방광벽, 후측면으로는 골반바닥(floor of pelvis), 근위면으로는 내장골동맥, 원위면으로는 Cooper 인대를 경계로 하고 있다. Choi 등[5]은 제한적 림프절 절제술을 해도 중간위험군 및 고위험군에서 정확한 병기 설정에 도움을 줄 수 있다고 주장하였으며 개복수술과 로봇수술을 비교한 결과 고위험군에서는 개복수술이 림프절절제술 시행에 더 효과적이었다고 보고하였다.

기존 가이드라인 요약 및 수용성, 적용성 평가

미국의 National Comprehensive Cancer Network (NCCN) 진료지침의 저자들은 골반림프절전이의 가능성이 2%보다 높은 경우 골반림프절절제술을 시행할 것을 권고하고 있으며 이러한 기준을 적용하면 47.7%의 불필요한 골반림프절절제술을 줄일 수 있는 반면 양성림프절을 놓치게 될 가능성은 12.1% 정도로 낮음을 근거로 하고 있다[6]. NCCN 패널들은 Memorial Sloan Kettering Cancer Center (MSKCC)에서 제시하는 기준을 권장하고 있다[6]. 이 경우 골반림프절절제술은 광범위 골반림프절절제술(extended PLND) 방식으로 시행하는 것이 추천된다[7,8]. 이는 절제 림프절의 수가 증가 할수록 림프절전이를 진단하게 될 가능성이 높아져 보다 정확한 병기를 설정할 수 있다는데 근거한다[9-11]. NCCN에서는 골반림프절절제술을 시행하는 것이 생존율에 이득을 준다는 보고들을 제시하고 있으며 이는 미세전이 림프절을 제거할 수 있기 때문인 것으로 해석하고 있다[10,12-14]. NCCN에서는 골반림프절절제술은 관혈적접근법, 복강경이나 로봇보조 접근법을 통한 근치전립선절제술 시행 시 모두에서 비교적 안전하게 시행할 수 있고 세 접근법 모두 골반림프절절제술로 인한 합병증의 발생률은 유사하다고 제시하였다.

EAU 가이드라인 역시 광범위 골반림프절절제술을 통해 예후에 대한 중요한 정보를 제공 받을 수 있음을 강조하며 중간위험도 전립선암 환자에 있어 골반림프절전이의 가능성이 5%보다 높은 경우 골반림프절절제술을 시행하는 것을 권고하고 있다. 이때 Briganti nomogram[15,16] 혹은 MSKCC 노모그람을 이용하여 림프절 전이 가능성을 예측할 것을 권장한다[17].

또한 AUA 가이드라인(2017)에서는 unfavorable 중간 위험도 전립선암(Gleason grade group 3) 환자에서 골반 림프절 절제술을 시행할 것을 권고하고 있다.

기존의 국내 전립선암 진료지침과 EAU 및 NCCN guideline에서는 골반림프절전이의 가능성이 2% (혹은 5%) 보다 높은 경우 골반림프절절제술을 시행하는 것을 권고하고 있다. 상기 연구결과들을 토대로 “기대여명이 10년 이상인 중간위험 전립선암 환자에서 근치적 전립선절제술 시행 시 림프절 전이의 가능성이 있는 경우 골반림프절 절제술을 권고한다.”라고 추천한다.

가이드라인 모두 수용 가능한 것으로 판단되고 적용성에 있어서 기존 치료 방법의 적용집단에 관한 문제로 특별한 문제는 없는 것으로 보인다.

업데이트 근거 요약

중간위험 그룹 중에서 소위 “low intermediate-risk” (글리슨 점수≤6, 임상병기≤2b, 전립선특이항원 10-20 ng/mL) 환자들의 경우 실제 림프절 전이가 3% 정도로 매우 낮게 보고된다. 이러한 환자군은 노모그람을 그대로 적용하여 골반임파선절제술을 시행하는 것에 신중을 기하는 것이 좋다[18,19].

참고문헌

1. Clark T, Parekh DJ, Cookson MS, Chang SS, Smith ER Jr, Wells N, et al. Randomized prospective evaluation of extended versus limited lymph node dissection in patients with clinically localized prostate cancer. J Urol 2003;169:145-7.

2. Briganti A, Giannarini G, Karnes RJ, Gandaglia G, Ficarra V, Montorsi F. What evidence do we need to support the use of extended pelvic lymph node dissection in prostate cancer? Eur Urol 2015;67:597-8.

3. Briganti A, Abdollah F, Nini A, Suardi N, Gallina A, Capitanio U, et al. Performance characteristics of computed tomography in detecting lymph node metastases in contemporary patients with prostate cancer treated with extended pelvic lymph node dissection. Eur Urol 2012;61:1132-8.

4. Kim KH, Lim SK, Kim HY, Shin TY, Lee JY, Choi YD, et al. Extended vs standard lymph node dissection in robot-assisted radical prostatectomy for intermediate- or high-risk prostate cancer: a propensity-score-matching analysis. BJU Int 2013;112:216-23.

5. Choi D, Kim D, Kyung YS, Lim JH, Song SH, You D, et al. Clinical experience with limited lymph node dissection for prostate cancer in Korea: single center comparison of 247 open and 354 robot-assisted laparoscopic radical prostatectomy series. Korean J Urol 2012;53:755-60.

6. Cagiannos I, Karakiewicz P, Eastham JA, Ohori M, Rabbani F, Gerigk C, et al. A preoperative nomogram identifying decreased risk of positive pelvic lymph nodes in patients with prostate cancer. J Urol 2003;170:1798-803.

7. Briganti A, Blute ML, Eastham JH, Graefen M, Heidenreich A, Karnes JR, et al. Pelvic lymph node dissection in prostate cancer. Eur Urol 2009;55:1251-65.

8. Heidenreich A, Ohlmann CH, Polyakov S. Anatomical extent of pelvic lymphadenectomy in patients undergoing radical prostatectomy. Eur Urol 2007;52:29-37.

9. Masterson TA, Bianco FJ Jr, Vickers AJ, DiBlasio CJ, Fearn PA, Rabbani F, et al. The association between total and positive lymph node counts, and disease progression in clinically localized prostate cancer. J Urol 2006;175:1320-4; discussion 1324-5.

10. Allaf ME, Palapattu GS, Trock BJ, Carter HB, Walsh PC. Anatomical extent of lymph node dissection: impact on men with clinically localized prostate cancer. J Urol 2004;172:1840-4.

11. Joslyn SA, Konety BR. Impact of extent of lymphadenectomy on survival after radical prostatectomy for prostate cancer. Urology 2006;68:121-5.

12. Bader P, Burkhard FC, Markwalder R, Studer UE. Disease progression and survival of patients with positive lymph nodes after radical prostatectomy. Is there a chance of cure? J Urol 2003;169:849-54.

13. Wagner M, Sokoloff M, Daneshmand S. The role of pelvic lymphadenectomy for prostate cancer--therapeutic? J Urol 2008;179:408-13.

14. Daneshmand S, Quek ML, Stein JP, Lieskovsky G, Cai J, Pinski J, et al. Prognosis of patients with lymph node positive prostate cancer following radical prostatectomy: long-term results. J Urol 2004;172:2252-5.

15. Briganti A, Larcher A, Abdollah F, Capitanio U, Gallina A, Suardi N, et al. Updated nomogram predicting lymph node invasion in patients with prostate cancer undergoing extended pelvic lymph node dissection:the essential importance of percentage of positive cores. Eur Urol 2012;61: 480-7.

16. Dell’Oglio P, Abdollah F, Suardi N, Gallina A, Cucchiara V, Vizziello D, et al. External validation of the European association of urology recommendations for pelvic lymph node dissection in patients treated with robot-assisted radical prostatectomy. J Endourol 2014;28: 416-23.

17. Hinev AI, Anakievski D, Kolev NH, Hadjiev VI. Validation of nomograms predicting lymph node involvement in patients with prostate cancer undergoing extended pelvic lymph node dissection. Urol int 2014;92:300-5.

18. Mandel P, Kriegmair MC, Veleva V, Salomon G, Graefen M, Huland H, et al. The role of pelvic lymph node dissection during radical prostatectomy in patients with Gleason 6 intermediate-risk prostate cancer. Urology 2016;93:141-6.

19. Fossati N, Willemse PM, Van den Broeck T, van den Bergh RCN, Yuan CY, Briers E, et al. The benefits and harms of different extents of lymph node dissection during radical prostatectomy for prostate cancer: a systematic review. Eur Urol 2017;72:84-109.

근거표

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KQ9
Reference	1. 1. Clark T, Parekh DJ, Cookson MS, Chang SS, Smith ER Jr, Wells N, et al. Randomized prospective evaluation of extended versus limited lymph node dissection in patients with clinically localized prostate cancer. J Urol 2003;169:145-7.
Study type	Randomized prospective study.
Patients	123 patients undergoing radical prostatectomy
Purpose of Study	To assess the value of an extended node dissection in detecting nodal metastasis
Study Results	Mean patient age was 61 years. Clinical stage was T1c in 88 patients (72%), T2a in 26 (21%), T2b in 7 (6%) and T3 in 2 (1%). Mean preoperative prostate specific antigen was 7.4 ng./ml. Pelvic lymph node metastasis was histologically confirmed in 8 patients (6.5%). Positive nodes were found on the side of the extended dissection in 4 patients, on the side of the limited dissection in 3 and on both sides in 1. Complications possibly attributable to the node dissection included lymphocele in 4 patients, lower extremity edema in 5, deep venous thrombosis in 2, ureteral injury in 1 and pelvic abscess in 1. These complications occurred 3 times more often on the side of the extended dissection (p=0.08).
Level of Study	1
Reference	2. Briganti A, Giannarini G, Karnes RJ, Gandaglia G, Ficarra V, Montorsi F. What evidence do we need to support the use of extended pelvic lymph node dissection in prostate cancer? Eur Urol 2015;67:597-8.
Study type	Expert opinion
Patients
Purpose of Study	To discuss the role of pelvic lymph node dissection (PLND) at the time of radical prostatectomy (RP)
Study Results	Even a prospective randomised trial might not provide a definitive answer as to the key clinical questions concerning the role of PLND at the time of RP, and might potentially lead to misleading conclusions. So what should we do? Knowledge of the biology of the disease should inform us on the type of treatment we should offer to our patients, and not vice versa. In this regard, novel biomarkers and genetic signatures may certainly help in closing this gap.
Level of Study	6
Reference	3. Briganti A, Abdollah F, Nini A, Suardi N, Gallina A, Capitanio U, et al. Performance characteristics of computed tomography in detecting lymph node metastases in contemporary patients with prostate cancer treated with extended pelvic lymph node dissection. Eur Urol 2012;61:1132-8.
Study type	Retrospective study
Patients	1541 patients undergoing radical prostatectomy and ePLND between 2003 and 2010 at a single center.
Purpose of Study	To assess the value of CT in predicting LNI in contemporary PCa patients treated with extended PLND (ePLND).
Study Results	Overall, a CT scan that suggested LNI was found in 73 patients (4.7%). Of them, only 24 patients (32.8%) had histologically proven LNI at ePLND. Overall, sensitivity, specificity, and accuracy of CT scan were 13%, 96.0%, and 54.6%, respectively. In patients with low-, intermediate-, or high-risk PCa according to NCCN classification, sensitivity was 8.3%, 96.3%, and 52.3%, respectively; specificity was 3.6%, 97.3%, and 50.5%, respectively; and accuracy was 17.9%, 94.3%, and 56.1%, respectively. Similarly, in patients with a nomogram-derived LNI risk ≥ 50%, sensitivity, specificity, and accuracy were only 23.9%, 94.7%, and 59.3%, respectively. At multivariable analyses, inclusion of CT scan findings did not improve the accuracy of LNI prediction (81.4% compared with 81.3%; p=0.8). Lack of a central scan review represents the main limitation of our study.
Level of Study	3
Reference	4. Kim KH, Lim SK, Kim HY, Shin TY, Lee JY, Choi YD, et al. Extended vs standard lymph node dissection in robot-assisted radical prostatectomy for intermediate- or high-risk prostate cancer: a propensity-score-matching analysis. BJU Int 2013;112:216-23.
Study type	Retrospective study
Patients	905 patients underwent robot-assisted radical prostatectomy and lymph node dissection (LND) by a single surgeon between June 2006 and January 2011
Purpose of Study	To To compare the pathological and biochemical outcomes between extended lymph node dissection (eLND) and standard lymph node dissection (sLND) in patients undergoing robot-assisted radical prostatectomy for intermediate- or high-risk prostate cancer.
Study Results	The median (range) follow-up period was 36 (12-77) months and the median number of lymph nodes removed was 21 and 12 in the eLND and sLND groups, respectively. Propensity-score matching resulted in 141 patients in each group. Although patients who underwent eLND had a higher clinical stage, biopsy Gleason score and number of positive cores than those treated with sLND in the entire cohort, there were no preoperative between-group differences in the matched cohort. In the matched cohort, lymph node metastases were detected at a significantly higher rate in the eLND than in the sLND group (12.1 vs. 5.0%, P=0.033). In the matched cohort, the 3-year biochemical recurrence-free survival rates were 77.8 and 73.5% in the eLND and sLND groups, respectively, which was not significant (hazard ratio 0.85, P=0.497).
Level of Study	3
Reference	5. Choi D, Kim D, Kyung YS, Lim JH, Song SH, You D, et al. Clinical experience with limited lymph node dissection for prostate cancer in Korea: single center comparison of 247 open and 354 robot-assisted laparoscopic radical prostatectomy series. Korean J Urol 2012;53:755-60.
Study type	Retrospective study
Patients	601 consecutive patients undergoing radical prostatectomy and bilateral limited PLND by either RRP (n=247) or RALP (n=354) in Asan Medical Center.
Purpose of Study	To demonstrate our clinical experience with limited PLND and the difference in its yield between open retropubic radical prostatectomy (RRP) and robot-assisted laparoscopic radical prostatectomy (RALP) for prostate cancer patients in Korea.
Study Results	The mean patient age was 64.9 years and the mean preoperative prostate-specific antigen was 9.8 ng/ml. The median number of removed lymph nodes per patient was 5 (range, 0 to 20). The numbers of patients of each risk group were 167, 199, and 238, and the numbers of patients with tumor-positive lymph nodes were 1 (0.6%), 4 (2.0%), and 17 (7.1%) in the low-, intermediate-, and high-risk groups, respectively. In the high-risk group, the lymph node-positive ratio was higher in RRP (14.9%) than in RALP subjects (2.4%).
Level of Study	3
Reference	6. Cagiannos I, Karakiewicz P, Eastham JA, Ohori M, Rabbani F, Gerigk C, et al. A preoperative nomogram identifying decreased risk of positive pelvic lymph nodes in patients with prostate cancer. J Urol 2003;170:1798-803.
Study type	Retrospective study
Patients	7,014 patients treated with radical prostatectomy at 6 institutions between 1985 and 2000.
Purpose of Study	To develope a preoperative nomogram for prediction of lymph node metastases in patients with clinically localized prostate cancer.
Study Results	Overall 5,510 patients with complete clinical and pathological information were included in the study. Lymph nodes metastases were present in 206 patients (3.7%). Pretreatment PSA, biopsy Gleason sum, clinical stage and institution represented predictors of lymph node status (p<0.001). Bootstrap corrected predictive accuracy of the 3-variable nomogram (clinical stage, Gleason sum and PSA) was 0.76. Inclusion of a fourth variable, which accounts for institutional differences in lymph node metastases, yielded an area under the receiver operating characteristics curve of 0.78. The negative predictive value of our nomograms was 0.99 when they predicted 3% or less chance of positive lymph nodes.
Level of Study	3
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