고위험도 전립선암 환자의 치료

KO 12. 고위험 전립선암 환자에서 외부 방사선 치료와 남성 호르몬 박탈요법을 병행한 군이 외 부 방사선 치료 단독군에 비해 생존율이 높은가? 

권고사항	권고수준	근거수준
고위험 전립선암 환자에서 외부 방사선 치료와 장기간(2-3년) 남성 호르몬 박탈요법을 병행한 군이 외부 방사선 치료 단독군에 비해 생존율이 높으므로, 고위험 전립선암 환자에서 외부 방사선 치료와 장기간 남성 호르몬 박탈요법을 권고한다.	A	I

개요

고위험 전립선암 환자에서 외부 방사선 치료의 효과는 이미 잘 확립이 되어 있다. European Organisation for Research and Treatment of Cancer (EORTC) 22863 연구에서는 415명의 전립선 암 환자를 외부 방사선 치료 단독군과 외부 방사선 치료와 남성 호르몬 박탈요법 병행군으로 무작위 배정한 후 10년 전반생존율(HR 0.60, 95% CI 0.45-0.80, p=0.0004), 10년 암 특이 생존율(HR 0.38, 95% CI 0.24-0.60, p<0.0001)이 모두 병행군에서 우월함을 보고하였다^[1]. 또한 EORTC 22961 연구에서는 970명의 국소적으로 진행한 전립선암 환자에서 6개월간 남성 호르몬 박탈요법을 병행한 군과 36개월간 병행한 군을 비교하였을 때 후자에서 5년 전반 사망률이 낮음을 보고하였다^[2].

또다른 대규모 전향적 무작위 연구인 NCIC Clinical Trials Group (NCIC CTG) PR.3/Medical Research Council (MRC) UK PR07 연구에서는 남성호르몬 박탈요법 단독군과 외부 방사선 치료와 남성 호르몬 박탈요법 병행군을 비교하였는데 전반생존율(HR 0.70, 95% CI, 0.57-0.85, p<0.001) 및 암 특이 생존율(HR 0.46, 95% CI 0.34-0.61, p<0.001)로 병행군에서 우월한 것으로 보고하였으며^[3,4] SPCG-7/SFUO-3 연구에서도 외부 방사선 치료와 남성 호르몬 박탈요법 병행군이 남성호르몬 박탈 요법 단독군에 비하여 좋은 예후를 보인다고 보고한 바 있다^[5]. 제시된 대부분의 연구에서 외부 방사선 치료와 남성 호르몬 박탈요법 병행이 암특이 생존율이나 전반 생존율에 있어 외부 방사선 치료 혹은 남성 호르몬 박탈요법 단일군보다 우월한 것으로 보고되었다^[6-9]. 최근 시행된 체계적 문헌고찰 및 메타분석에서도 고위험 전립선암 환자에서는 근치적 전립선적출술 혹은 방사선 치료 후 장기간 남성호르몬 박탈요법의 시행이 가장 좋은 종양학적 결과를 보여주는 치료 옵션이라고 하였다^[10].

기존 가이드라인 요약 및 수용성, 적용성 평가

NCCN 가이드라인에서는 고위험 전립선암 환자에서 외부 방사선 치료와 장기간(2-3년) 남성 호르몬 박탈요법을 병행하는 것을 category 1으로 권고하고 있다^[3-5,7]. EAU 진료지침에서도 고위험 전립선암 환자에서 76-78 Gy의 외부 방사선 치료와 장기간(2-3년) 남성 호르몬 박탈요법이 생존율 향상에 도움이 된다고 권고하고 있다^[11].

상기 연구결과들을 토대로^[11-13] “고위험 전립선암 환자에서 외부 방사선 치료와 장기간(2-3년) 남성 호르몬 박탈요법을 병행한 군이 외부 방사선 치료 단독군에 비해 생존율이 높으므로 고위험 전립선암 환자에서 외부 방사선 치료와 장기간 남성 호르몬 박탈요법이 권고된다.”라고 추천한다.

KQ 12. 고위험 전립선암 환자에서 외부 방사선 치료와 남성 호르몬 박탈요법을 병행한 군이 외부 방사선 치료 단독군에  비해 생존율이 높은가?
지침(제목)	권고	권고등급	근거수준	page
1. 2015 KUOS	외부 방사선치료를 하는 경우 남성호르몬박탈요법을 장기 간 병행하도록 한다. 고위험 전립선암에서는 치료 전후로 남 성호르몬박탈요법도 동시에 시행하는 것이 치료 효과를 높 인다고 알려져 있다. 이 경우 단기간의 사용보다는 장기간 병행하는 것이 더 좋은 결과를 보여주는 경우가 많이 보고된 다. EORTC 22961 연구에서는 960명의 국소적으로 진행한 전립선암 환자에서 6개월간 남성호르몬 박탈요법을 병행한 군과 36개월간 병행한 군을 비교하였을 때 후자에서 5년째 전체 생존율이 더 우수하였다.	n/c	1b	28
2. EAU 2016	고위험 전립선암 환자에서 76-78Gy의 외부 방사선 치료와 장기간(2-3년) 남성 호르몬 박탈요법이 생존율 향상에 도움이 된다.	A	1b	48
3. AUA 2007	외부 방사선 치료를 고려하는 고위험 전립선암 환자에서 외 부 방사선 치료와 남성 호르몬 박탈요법 병합이 생존율 향상 에 도움이 될 수 있다.	n/c	n/c	31
5. NCCN 2016	외부 방사선치료를 하는 경우 남성호르몬박탈요법을 장기간 병행하도록 한다. 고위험 전립선암에서는 치료 전후로 남성 호르몬 박탈요법도 동시에 시행하는 것이 치료 효과를 높인 다고 알려져 있다.		Category  1:	PROS-5(11)

지침(제목)		1. 2015 KUOS	2. EAU 2016	3. AUA 2007	5. NCCN 2016
수용성	인구 집단(유병률, 발생률 등)이 유사하다.	예	예	예	예
	가치와 선호도가 유사하다.	예	예	예	예
	권고로 인한 이득은 유사하다	예	예	예	예
	해당 권고는 수용 할 만하다.	예	예	예	예
적용성	해당 중재/장비는 이용 가능하다.	예	예	예	예
	필수적인 전문기술이 이용 가능하다.	예	예	예	예
	법률적/제도적 장벽이 없다.	예	예	예	예
	해당 권고는 적용 할 만하다.	예	예	예	예

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

업데이트 근거 요약

고위험 전립선암 환자에서 외부 방사선 치료를 할 때 적어도 75.6 cGy의 조사량이 필요하며^[14] 메타 분석에서 외부 방사선 치료와 장기간 남성 호르몬 박탈요법을 병행한 군이 호르몬 단독 혹은 근접 방사선 치료(brachytherapy) 보다 생존율 향상에 도움이 된다고 보고하였다^[15]. 최근에는 외부 방사선 치료와 남성 호르몬 박탈요법이 N0M0 병기 뿐만 아니라 N1 병기 환자에서도 이득이 있다는 결과가 보고 되었다^[16,17].

최근 여러 논문에서도 고위험 전립선암 환자에서 외부 방사선 치료와 장기간(2-3년) 남성 호르몬 박탈요법을 병행한 군이 외부 방사선 치료 및 남성 호르몬 박탈요법 단독군에 비해 생존율이 높으므로^[3,18-20] 고위험 전립선암 환자에서 외부 방사선 치료와 장기간 남성 호르몬 박탈요법이 권고된다.

참고문헌

1. Bolla M, Van Tienhoven G, Warde P, et al. External irradiation with or without long-term androgen suppression for prostate cancer with high metastatic risk: 10-year results of an EORTC randomised study. Lancet Oncol 2010:11(11):1066-73,

2. Bolla M, de Reijke TM, Van Tienhoven G, et al. Duration of androgen suppression in the treatment of | prostate cancer, N Engl J Med 2009:360(24):2516-27.

3. Mason MD, Parulekar WR, Sydes MR, et al. Final Report of the Intergroup Randomized Study of Combined Androgen-Deprivation Therapy Plus Radiotherapy Versus Androgen-Deprivation Therapy Alone in Locally Advanced Prostate cancer. J Clin Oncol 2015:33(19):2143-50.

4. Warde P, Mason M, Ding K, et al. Combined androgen deprivation therapy and radiation therapy for locally advanced prostate cancer: a randomised, phase 3 trial. Lancet 2011:378(9809):2104-11.

5. Widmark A, Klepp O, Solberg A, et al. Endocrine treatment, with or without radiotherapy, in locally advanced prostate cancer (SPCG-7/SFUO-3): an open randomised phase III trial. Lancet 2009:373(9660): 301-8.

6. Horwitz EM, Bae K, Hanks GE, et al. Ten-year follow-up of radiation therapy oncology group protocol 92 02:a phase III trial of the duration of elective androgen deprivation in locally advanced prostate cancer. J Clin Oncol 2008;26(15):2497-504.

7. Zapatero A, Guerrero A, Maldonado X, et al. High-dose radiotherapy with short-term or long-term androgen deprivation in localised prostate cancer (DART01/05 GICOR): a randomised, controlled, phase 3 trial. Lancet Oncol 2015:16(3):320-7.

8. Souhami L, Bae K, Pilepich M, Sandler H. Impact of the duration of adjuvant hormonal therapy in patients with locally advanced prostate cancer treated with radiotherapy: a secondary analysis of RTOG 85-31. J Clin Oncol 2009;27(13):2137-43.

9. Pilepich MV, Winter K, Lawton CA, et al. Androgen suppression adjuvant to definitive radiotherapy in prostate carcinoma--long-term results of phase III RTOG 85-31. Int J Radiat Oncol Biol Phys 2005;61(5): 1285-90.

10. Lei JH, Liu LR, Wei Q, et al. Systematic review and meta-analysis of the survival outcomes of first-line treatment options in high-risk prostate cancer. Sci Rep 2015;5:7713.

11. Network NCC. NCCN Clinical Practice Guidelines in Oncology Prostate Cancer Version 3.2016. May 2016. 2016.

12. Mottet N, Bellmunt J, Bolla M, et al. EAU-ESTRO-SIOG guidelines on prostate cancer. Part 1: screening, diagnosis, and local treatment with curative intent. European Urology 2017;71(4):618-29.

13. Thompson I, Thrasher J. Aus G, et al. American Urological Association guideline for management of clinically localized prostate cancer: 2007 update. 2007. 2014.

14. Mohiuddin JJ, Baker BR, Chen RC. Radiotherapy for high-risk prostate cancer. Nat Rev Urol 2015;12(3):145 54.

15. Lei JH, Liu LR, Wei Q et al Systematic review and meta-analysis of the survival outcomes of first-line treatment options in high-risk prostate cancer. Sci Rep 2015;5:7713.

16. James ND, Spears MR, Clarke NW, et al. Failure-Free Survival and Radiotherapy in Patients With Newly Diagnosed Nonmetastatic Prostate cancer: Data From Patients in the Control Arm of the STAMPEDE Trial. JAMA Oncol 2016;2(3):348-57.

17. Wong AT, Schwartz D, Osborn V, et al. Adjuvant radiation with hormonal therapy is associated with improved survival in men with pathologically involved lymph nodes after radical surgery for prostate cancer. Urol Oncol 2016:34(12):529.

18. Rose BS, Chen MH, Wu J, et al. Androgen Deprivation Therapy Use in the Setting of High-dose Radiation Therapy and the risk of Prostate Cancer-Specific Mortality Stratified by the Extent of Competing Mortality. Int J Radiat Oncol Biol Phys 2016:96(4):778-784. Urol Oncol 2016:34(12):529.e15-529.

19. Kasuya G, Ishikawa H, Tsuji H, et al. Cancer-specific mortality of high-risk prostate cancer after carbon-ion radiotherapy plus long-term androgen deprivation therapy. Cancer Sci 2017:108(12):2422-9.

20. Royce TJ, Chen MH, Wu J, et al, Surrogate End Points for All-Cause Mortality in Men With Localized Unfavorable-Risk Prostate Cancer Treated With Radiation Therapy vs Radiation Therapy Plus Androgen Deprivation Therapy: A Secondary Analysis of a Randomized Clinical Trial. JAMA Oncol 2017:3(5):652-8.  

근거표

KQ12
Reference	1. Bolla M, Van Tienhoven G, Warde P, et al. External irradiation with or without long-term androgen suppression for prostate cancer with high metastatic risk: 10-year results of an EORTC randomised study. Lancet Oncol 2010;11(11):1066-73.
Study type	Randomized study
Patients	415 patients
Purpose of Study	To present the 10-year results of European Organisation for Research and Treatment of Cancer (EORTC) 22863, with the aim of confi rming whether previously reported improvements in overall survival were sustained and assessing the effect of the treatment on long-term cardiovascular morbidity and bone fractures.
Study Results	Between May 22, 1987, and Oct 31, 1995, 415 patients were randomly assigned to treatment groups and were included in the analysis (208 radiotherapy alone, 207 combined treatment). Median follow-up was 9.1 years (IQR 5.1-12.6). 10-year clinical disease-free survival was 22.7% (95% CI 16.3-29.7) in the radiotherapy-alone group and 47.7% (39.0-56.0) in the combined treatment group (hazard ratio [HR] 0.42, 95% CI 0.33-0.55, p<0.0001). 10-year overall survival was 39.8% (95% CI 31.9-47.5) in patients receiving radiotherapy alone and 58.1% (49.2-66.0) in those allocated combined treatment (HR 0.60, 95% CI 0.45-0.80, p=0.0004), and 10-year prostate-cancer mortality was 30.4% (95% CI 23.2-37.5) and 10.3% (5.1-15.4), respectively (HR 0.38, 95% CI 0.24-0.60, p<0.0001). No significant difference in cardiovascular mortality was noted between treatment groups both in patients who had cardiovascular problems at study entry (eight of 53 patients in the combined treatment group had a cardiovascular-related cause of death vs 11 of 63 in the radiotherapy group; p=0.60) and in those who did not (14 of 154 vs six of 145; p=0.25). Two fractures were reported in patients allocated combined treatment.
Level of Study	1
Reference	2. Bolla M, de Reijke TM, Van Tienhoven G, et al. Duration of androgen suppression in the treatment of prostate cancer. N Engl J Med 2009;360(24):2516-27.
Study type	Randomized study
Patients	970 patients
Purpose of Study	We compared the use of radiotherapy plus short-term androgen suppression with the use of radiotherapy plus long-term androgen suppression in the treatment of locally advanced prostate cancer.
Study Results	A total of 1113 men were registered, of whom 970 were randomly assigned, 483 to short- term suppression and 487 to long-term suppression. After a median follow-up of 6.4 years, 132 patients in the short-term group and 98 in the long-term group had died; the number of deaths due to prostate cancer was 47 in the short-term group and 29 in the long-term group. The 5-year overall mortality for short-term and long-term suppression was 19.0% and 15.2%, respectively; the observed hazard ratio was 1.42 (upper 95.71% confidence limit, 1.79; P=0.65 for noninferiority). Adverse events in both groups included fatigue, diminished sexual function, and hot flushes.
Level of Study	1
Reference	3. Mason MD, Parulekar WR, Sydes MR, et al. Final Report of the Intergroup Randomized Study of Combined Androgen-Deprivation Therapy Plus Radiotherapy Versus Androgen- Deprivation Therapy Alone in Locally Advanced Prostate Cancer. J Clin Oncol. 2015 Jul 1;33(19):2143-50.
Study type	Randomized controlled trial
Patients	1,205 patients
Purpose of Study	We have previously reported that radiotherapy (RT) added to androgen-deprivation therapy (ADT) improves survival in men with locally advanced prostate cancer. Here, we report the prespecified final analysis of this randomized trial.
Study Results	One thousand two hundred five patients were randomly assigned between 1995 and 2005, 602 to ADT alone and 603 to ADT+RT. At a median follow-up time of 8 years, 465 patients had died, including 199 patients from prostate cancer. Overall survival was significantly improved in the patients allocated to ADT+RT (hazard ratio [HR], 0.70; 95% CI, 0.57 to 0.85; P < .001). Deaths from prostate cancer were significantly reduced by the addition of RT to ADT (HR, 0.46; 95% CI, 0.34 to 0.61; P < .001). Patients on ADT+RT reported a higher frequency of adverse events related to bowel toxicity, but only two of 589 patients had grade 3 or greater diarrhea at 24 months after RT.
Level of Study	1
Reference	4. Warde P, Mason M, Ding K, et al. Combined androgen deprivation therapy and radiation therapy for locally advanced prostate cancer: a randomised, phase 3 trial. Lancet. 2011 Dec 17;378(9809):2104-11.
Study type	Prospective single-arm cohort study
Patients	Patients with: locally advanced (T3 or T4) prostate cancer (n=1,057); or organ-confined disease (T2)
Purpose of Study	Whether the addition of radiation therapy (RT) improves overall survival in men with locally advanced prostate cancer managed with androgen deprivation therapy (ADT) is unclear. Our aim was to compare outcomes in such patients with locally advanced prostate cancer.
Study Results	Between 1995 and 2005, 1205 patients were randomly assigned (602 in the ADT only group and 603 in the ADT and RT group); median follow-up was 6.0 years (IQR 4.4-8.0). At the time of analysis, a total of 320 patients had died, 175 in the ADT only group and 145 in the ADT and RT group. The addition of RT to ADT improved overall survival at 7 years (74%, 95% CI 70-78 vs 66%, 60-70; hazard ratio [HR] 0.77, 95% CI 0.61-0.98, p=0.033). Both toxicity and health-related quality-of-life results showed a small effect of RT on late gastrointestinal toxicity (rectal bleeding grade >3, three patients (0.5%) in the ADT only group, two (0.3%) in the ADT and RT group; diarrhoea grade >3, four patients (0.7%) vs eight (1.3%); urinary toxicity grade >3, 14 patients (2.3%) in both groups).
Level of Study	1
Reference	5. Widmark A, Klepp O, Solberg A, et al. Endocrine treatment, with or without radiotherapy, in locally advanced prostate cancer (SPCG-7/SFUO-3): an open randomised phase III trial. Lancet. 2009 Jan 24;373(9660):301-8.
Study type	Randomized controlled trial
Patients	875 patients with locally advanced prostate cancer
Purpose of Study	To assess the effect of radiotherapy, we did an open phase III study comparing endocrine therapy with and without local radiotherapy, followed by castration on progression.
Study Results	After a median follow-up of 7.6 years, 79 men in the endocrine alone group and 37 men in the endocrine plus radiotherapy group had died of prostate cancer. The cumulative incidence at 10 years for prostate-cancer-specific mortality was 23.9% in the endocrine alone group and 11.9% in the endocrine plus radiotherapy group (difference 12.0%, 95% CI 4.9-19.1%), for a relative risk of 0.44 (0.30-0.66). At 10 years, the cumulative incidence for overall mortality was 39.4% in the endocrine alone group and 29.6% in the endocrine plus radiotherapy group (difference 9.8%, 0.8-18.8%), for a relative risk of 0.68 (0.52- 0.89). Cumulative incidence at 10 years for PSA recurrence was substantially higher in men in the endocrine-alone group (74.7%vs 25.9%, p<0.0001; HR 0.16; 0.12-0.20). After 5 years, urinary, rectal, and sexual problems were slightly more frequent in the endocrine plus radiotherapy group.
Level of Study	1
Reference	6. Lei JH, Liu LR, Wei Q, et al. Systematic review and meta-analysis of the survival outcomes of first-line treatment options in high-risk prostate cancer. Sci Rep. 2015 Jan 12;5:7713.
Study Results	Systematic review and meta-analysis
Patients
Purpose of Study	To compare the long-term survival outcomes of radical prostatectomy (RP), radiation therapy (RT), brachytherapy (BT), androgen- deprivation therapy (ADT), and watchful waiting (WW) in high-risk prostate cancer (PCa).
Study Results	A RCT conducted by Bolla et al. reported that RT plus 3-yr aADT resulted in a significantly better 5-yr OS than RT alone (79% for the combination vs. 62% for RT, P=0.001). D’Amico et al. also performed a comparison between RT and RT plus 6-mo aADT. Significant difference was also found for 5-yr OS (88% vs. 78%, P=0.04). Pilepich et al. also reported a better CSS using RT plus aADT (63.5% vs. 48.2% P=0.01) than RT alone. Similarly, Miljenko, et al. revealed a better outcome using RT plus (n+c) ADT, although the difference was not significant (8-yr OS 38% vs. 31%, P=0.98; 8-yr CSM 44% vs. 54%, P=0.36).
Level of Study	1

KO 13. 고위험 전립선암 환자에서 근치적 전립선 절제술 시행 시 확장 골반림프절절제술 (extended pelvic ymph node dissection)을 시행한 경우는 확장 골반림프절절제술을 시행하지 않은 경우에 비해 생존율이 높은가?  

권고사항	권고수준	근거수준
고위험 전립선암 환자에서 근치적 전립선 절제술과 함께 시행하는 확장 골반 림프절절제술(extended pelvic lymph node dissection)이 환자의 생존율을 높인다고 할 수는 없으나 정확한 병기 결정을 위해서 도움이 되므로 확장 골반 림프절절제술 시행을 고려할 수 있다.	C	III

개요

고위험 전립선암 환자들은 PSA 실패나 이차 치료의 필요, 질병의 진행 또는 전이 및 전립선암으로 인한 사망의 가능성이 높은 환자군이다. 모든 고위험 전립선암 환자들이 다 좋지 않은 경과를 보이는 것은 아니지만 보존적 방법으로 질환을 치료할 경우 이 환자들의 10년 및 15년 전립선암 특이 사망률 은 각각 28.8% 및 35.5%였다^[1]. 고위험 전립선암에 대해 정해진 표준 치료법은 없지만 한 연구에서 는 림프절 전이의 확률이 15-40%인 경우 확장 골반림프절절제술을 시행해야 한다고 주장한 바 있다^[2].

확장 골반림프절절제술의 범위는 외장골동/정맥, 폐쇄 신경 주위, 내장골동맥의 내/외측을 포함하는데 이 부위 외에 총장골 및 천골 앞 부위까지 포함하여 림프절을 제거해야 더 완전한 림프절절제술이라는 의견도 있다. 유럽비뇨기과학회 전립선암 가이드라인 2016년 판에서는 각각의 부위를 별도의 통에 담아 병리과로 보내는 것을 권고하고 있다.

기존 가이드라인 요약 및 수용성, 적용성 평가  

확장 골반림프절절제술을 시행하면 제한 골반림프절절제술을 시행하는 것에 비해 약 2배 정도 림프절 전이를 더 잘 발견할 수 있어 정확한 병기 결정이 가능하다고 하였다^[3,4]. 또한, 확장된 림프절 절 제술을 통한 생존율의 증가가 몇몇 후향적 연구에서 관찰되었는데 그 이유는 현미경적 전이가 제거되었기 때문으로 생각된다^[5,6].

이러한 연구 결과들에 의거하여 국내 2015 KUOS 전립선암진료지침에서는 고위험 전립선암 환자군에서 확장 골반림프절 절제술을 시행할 것을 권고하고 있다. 2016 유럽비뇨기과학회 전립선암 가 이드라인 2016년 판에서는 Briganti, MSKCC, 또는 Roach 노모그램(nomogram)에서 림프절 전이의 가능성이 5% 이상일 경우 확장 골반림프절절제술을 시행해야 한다고 권고하였다. NCCN 2016 전립선암 가이드라인에서는 고위험군에서의 치료 방법 중 하나로 전립선절제술 및 골반림프절절제술을 권고하고 있으나, AUA 2007 전립선암 가이드라인에서는 고위험군 전립선암에 대한 기술이 별도로 없다. Cancer Council Australia/Australian Cnacer Network (CCAACN) 2010 국소 진행성 전립선 암 가이드라인에서는 표준 골반림프절 절제술과 확장 골반림프절 절제술의 효용성을 비교한 무작위 연구는 아직까지 없다고 기술하고 있다. 요약하면 고위험 전립선암 환자군에서 확장 골반림프절 절제술을 시행하는 것이 생존율을 높인다고 할 수는 없으나 정확한 병기 결정을 위해서 도움이 되므로 이러한 환자군에 대해 확장 골반림프절절제술 시행을 고려할 수 있다.

KQ 13. 고위험 전립선암 환자에서 근치적 전립선 절제술 시행 시 확장 골반림프절절제술(extended pelvic lymph node  dissection)을 시행한 경우는 확장 골반림프절절제술을 시행하지 않은 경우에 비해 생존율이 높은가?
지침(제목)	권고	권고등급	근거수준	page
1. 2015 KUOS	생존율에 대한 내용 없음. 참고) 골반림프절절제술 (pelvic lymph node dissection)의 치료 효과 에 대해서는 논란이 있으나, 최근 시행된 한 단일기관 전향적 무작위 연구에서 확장 골반림프절 절제술을 시행할 시 고위험 전립선암에서 제한 골반림프절절제술을 시행한 것에 비하여 생화학적 재 발의 결과가 우수한 것으로 보고되었다. 따라서 고위험 전 립선암환자에서 선별적으로 근치전립선절제술을 시행할 시 확장 골반림프절절제술 (extended pelvic lymph node dissection)을 시행하여야 한다. 골반림프절절제술의 치료적 인 효과에 대해서는 아직 논란이 많은 상황인데, 최근에 중 국에서 보고 된 무작위 연구에서 중등도 혹은 고위험 전립선 암 환자에서는 생화학적 재발율 성적이 제한 골반림프절절 제술을 시행한 그룹보다 확장 골반림프절절제술을 시행한 그룹이 더 우수함을 보고하였다.	n/c	n/c	29, 31
2. EAU 2016	Extended LND should be performed in all high-risk PCa cases, as the estimated risk for positive lymph nodes is 15-40% [328]. (p33) Indication and extent of pelvic lymph node dissection. It is generally accepted that extended pelvic lymph node dissection (eLND) provides important information for prognosis which cannot be matched by any other currently available procedure [245]. (p34) In another series, it was demonstrated that a more extensive LND was associated with improvement in CSS in patients with lymph node invasion [370]. Retrospective findings suggest, but do not prove that men with nodal metastases may benefit from more extended nodal dissection. (p35) 림프절 전이가 있는 전립선암 환자에서 더 광범위한 extended LND를 시행한 경우 종양 특이 생존율이 높았다.	n/c	3	33-35
3. AUA 2007	Pelvic lymphadenectomy can be performed concurrently with radical prostatectomy and is generally reserved for patients with higher risk of nodal involvement. 골반 림프 절 절제술은 림프절 전이가 많이 의심되는 경우 근치적 전립 선 절제술과 동시에 시행되어야 한다.	n/c	n/c	14
5. NCCN 2016	고위험군에서의 치료 방법 중 하나로 전립선절제술 및 골반 림프절절제술을 권고하고 있음. 참고) An extended PLND will discover metastases approximately twice as often as a limited PLND. Extended PLND provides more complete staging and may cure some men with microscopic metastases; therefore, an extended PLND is preferred when PLND is performed. (Pros-E page) 확장된 PNLD 는 제한된 PNLD 보다 2 배 정도의 전이를 발견한다. 확장 된 PLND는 병기 설정을 보다 정확하게 하고 현미경적전이 가 있는 일부 남성을 치료할 수 있다. 그러므로, PLND 시 행 시에는 확장 PLND가 바람직하다. A survival advantage with more extensive lymphadenectomy has been suggested by several studies, possibly due to elimination of microscopic metastases. (MS 13) 확장된 림프절 절제 술을 통한 생존율의 증가가 몇몇 연구에서 관찰되었는데, 기 전은 현미경적 전이가 제거됨으로 생각되고 있다. (MS13)	n/c	n/c	Pros-E,  MS  12-13
9. CCAACN 2010	For locally advanced disease there are no RCTs examining the efficacy of extended lymph node dissection compared with standard lymph node dissection. 국소진행성 전립선암에서 표준 림프절 절제술과 광범위 림프절 절제술의 효용성을 비교한 무작위 연구는 아 직까지 없다.	n/c	2	33

지침(제목)		1. 2015 KUOS	2. EAU 2016	3. AUA 2007	5. NCCN 2016	9. CCAACN 2010
수용성	인구 집단(유병률, 발생률 등)이 유사하다.	예	아니오	아니오	아니오	아니오
	가치와 선호도가 유사하다.	예	예	예	예	예
	권고로 인한 이득은 유사하다	예	예	예	예	예
	해당 권고는 수용 할 만하다.	예	예	예	예	예
적용성	해당 중재/장비는 이용 가능하다.	예	예	예	예	예
	필수적인 전문기술이 이용 가능하다.	예	예	예	예	예
	법률적/제도적 장벽이 없다.	예	예	예	예	예
	해당 권고는 적용 할 만하다.	예	예	예	예	예

가이드라인 모두 수용 가능한 것으로 판단되고 적용성에 있어서 기존 치료 방법의 적용 집단에 관 한 특별한 문제는 없는 것으로 보인다. 

업데이트 근거 요약  

Abdollah 등은 315명의 림프절 전이가 있는 전립선암 환자들에 대해 전립선절제술 및 확장 림프절 절제술을 시행한 후 제거된 림프절의 수와 질병특이생존율과의 관계를 분석한 후향적 연구 결과를 2015년 발표하였다. 그들의 연구 결과에 의하면 중간 추적 기간 54개월 하에서 10년 질병특이생존율 은 제거된 림프절 개수가 8개일 때 75%였으나 45개였을 때 98%로 림프절 제거를 많이 할수록 질병 특이생존율이 증가함을 보고하였고 제거된 림프절 개수가 질병특이생존율을 낮추는 유의한 인자임 을 보고하였다^[7]. Ledezma 등이 수행한 로봇 전립선절제술 및 확장 림프절 절제술에 대한 다기관 연구에서 림프절 전이가 있는 환자들의 경우 1년 생화학적 무재발 생존율이 42%, 3년 생화학적 무재발 생존율이 28%라고 하였고, 림프절 전이가 2개 이하 및 글리손 점수 7점 이하인 경우 보조적 치료 없 이 생화학적 재발에 대한 성적이 좋음을 보고하였다^[8]. 림프절 전이가 있는 전립선암에 대해 전립선 절제술과 확장 골반림프절제술을 시행한 결과를 보고한 또 다른 후향적 연구에서 평균 추적 기간 5.3 년 기간 동안 질병 특이생존율은 8.8년, 질병 특이 사망률 13.6%로 확장 골반림프절절제술이 이러한 환자군에서의 적절한 치료법이 될 수 있음을 시사하였다^[9]. 1,586명의 국소 진행성 병기 이상의 전립선암 환자들에서의 전립선절제술과 확장 골반림프절제술의 효용성을 분석한 Moschini의 연구에서 제거된 림프절의 개수 및 보조 방사선 치료 시행 여부가 질병 특이 사망률을 낮추어 주는 유의한 인자들이라고 하였다^[10]. Narita 등은 확장 골반림프절절제술과 신보조 치료(남성호르몬 차단 요법 및 estramustine 투여) 및 제한 골반림프절절제술과의 종양학적 결과를 분석한 비 무작위 후향적 연구 결 과를 보고하였는데 5년 생화학적 무재발 생존율이 각각 55%, 85%로 신보조 치료 및 제한 골반림프 절절제술의 성적이 유의하게 더 좋음을 보고하였다^[11]. 또한 확장 골반림프절절제술이 제한 골반림프절절제술에 비해 더 많은 림프절 절제가 가능하고 림프절 전이 여부에 대해 더 정확하게 알 수 있다는 것이 2017년 체계적인 문헌 고찰을 통해 밝혀졌다^[12].

림프절 전이가 있는 전립선암의 경우 림프절 전이 개수가 많은 경우 치료 예후가 안 좋고 림프절 제거를 많이 할수록 질병 특이 생존율이 증가한다는 연구 결과는 앞에서 언급한 것처럼 많이 보고되었지만 제한 골반림프절절제술과 비교하여 확장 골반림프절절제술의 생존율의 향상에 대한 전향적 연구가 없었기 때문에 확장 골반림프절절제술이 생존율을 높인다고 단언할 수는 없겠다. 하지만 확장 골반림프절절제술 시행은 정확한 병기 결정에 도움이 되고 이로 인해 치료 예후 및 방법을 결정하는데 도움이 될 수 있으므로 고위험 전립선암 환자에 대해 근치적 전립선 절제술 시행 시 확장 골반림프절절제술 시행을 고려할 수 있을 것이다.

참고문헌

1. Rider JR, et al. Long-term outcomes among noncuratively treated men according to prostate cancer risk category in a nationwide, population-based study. Eur Urol 2013;63:88.

2. Briganti A, 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.

3. Heidenreich A, Varga Z, Von Knobloch R. Extended pelvic lymphadenectomy in patients undergoing radical prostatectomy: high incidence of lymph node metastasis. J Urol 2002;167:1681-6.

4. Kim KH, Lim SK, Kim HY, 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. Joslyn SA, Konety BR. Impact of extent of lymphadenectomy on survival after radical prostatectomy for prostate cancer. Urology 2006;68(1):121-5. Epub 2006 Jun 27.

6. Wagner M, Sokoloff M, Daneshmand S. The role of pelvic lymphadenectomy for prostate cancer-- therapeutic? J Urol 2008:179(2):408-13.

7. Abdollah F, Gandaglia G, Suardi N, Capitanio U, Salonia A, Nini A, Moschini M, Sun M, Karakiewicz PI, Shariat SF, Montorsi F, Briganti A. More extensive pelvic lymph node dissection improves survival in patients with node-positive prostate cancer. Eur Urol 2015:67(2):212-9.

8. Ledezma RA, Negron E, Razmaria AA, Dangle P, Eggener SE, Shalhav AL, Zagaja GP. Robotic-assisted pelvic lymph node dissection for prostate cancer: frequency of nodal metastases and oncological outcomes. World Journal of Urology 2015:33(11):1689-94.

9. Muck A, Langesberg C, Mugler M, Rahnenführer J, Wullich B, Schafhauser W. Clinical outcome of patients with lymph node-positive prostate cancer following radical prostatectomy and extended sentinel lymph node dissection. Urol Int 2015:94(3):296-306.

10. Moschini M, Fossati N, Abdollah F, Gandaglia G, Cucchiara V, Dell'Oglio P, Luzzago S, Shariat SF, Dehò F, Salonia A, Montorsi F, Briganti A. Determinants of long-term survival of patients with locally advanced prostate cancer: the role of extensive pelvic lymph node dissection. Prostate Cancer Prostatic Dis 2016;19(1):63-7.

11. Narita T, Koie T, Ookubo T, Mitsuzuka K, Narita S, Yamamoto H, Inoue T, Hatakeyama S, Kawamura S, Tochigi T, Habuchi T, Arai Y, Ohyama C. The impact of extended lymph node dissection versus neoadjuvant therapy with limited lymph node dissection on biochemical recurrence in high-risk prostate cancer patients treated with radical prostatectomy: a multi-institutional analysis. Med Oncol 2017:34(1):1.

12. Fossati N, Willemse PM, Van den Broeck T, van den Bergh RCN, Yuan CY, Briers E, Bellmunt J, Bolla M, Cornford P, De Santis M, MacPepple E, Henry AM, Mason MD, Matveev VB, van der Poel HG, van der Kwast TH, Rouvière O, Schoots IG, Wiegel T, Lam TB, Mottet N, Joniau S. The Benefits and Harms of Different Extents of Lymph Node Dissection During Radical Prostatectomy for Prostate Cancer: A Systematic Review. Eur Urol 2017:72(1):84-109. 

근거표

KQ13
Reference	1. Abdollah F, Gandaglia G, Suardi N, Capitanio U, Salonia A, Nini A, Moschini M, Sun M, Karakiewicz PI, Shariat SF, Montorsi F, Briganti A More extensive pelvic lymph node dissection improves survival in patients with node-positive prostate cancer. Eur Urol 2015;67(2):212-9.
Study type	Multicenter longitudinal Observational Study
Patients	315 pN1 PCa patients treated with radical prostatectomy (RP) and anatomically ePLND between 2000 and 2012 at one tertiary care centre
Purpose of Study	The relationship between the number of removed lymph nodes (RLNs) and cancer-specific mortality (CSM) was tested in patients with LNI
Study Results	The average number of RLNs was 20.8 (median: 19; interquartile range: 14-25). Mean and median follow-up were 63.1 and 54 mo, respectively. At 10-yr, the CSM-free survival rate was 74.7%, 85.9%, 92.4%, 96.0%, and 97.9% for patients with 8, 17, 26, 36, and 45 RLNs, respectively. By multivariable analyses, the number of RLNs independently predicted lower CSM rate (hazard ratio [HR]: 0.93; p=0.02). Other predictors of CSM were Gleason score 8-10 (HR: 3.3), number of positive nodes (HR: 1.2), and aRT treatment (HR: 0.26; all p≤0.006). The study is limited by its retrospective nature.
Level of Study	4
Reference	2. Ledezma RA, Negron E, Razmaria AA, Dangle P, Eggener SE, Shalhav AL, Zagaja GP. Robotic-assisted pelvic lymph node dissection for prostate cancer: frequency of nodal metastases and oncological outcomes. World Journal of Urology 2015;33(11):1689-94.
Study type	Multicenter longitudinal observational Study
Patients	1,740 consecutive patients who underwent RALP and extended PLND
Purpose of Study	determine the frequency of pelvic lymph node metastasis and oncological outcomes following RALP with PLND in patients who did not receive adjuvant androgen deprivation therapy (ADT)
Study Results	One hundred and eight patients (6%) with positive LNs were identified. The median number of LNs removed was 17 (IQR 11-24), and median follow-up was 26 months (IQR 14-43). Ninety-one (84%) patients did not receive adjuvant ADT of whom 60% had BCR with a median time to recurrence of 8 months. The 1- and 3-year BCR-free probability was 42 and 28%, respectively. Patients with <=2 LN+ had significantly better biochemicalfree estimated probability compared to those with >2 LN+ (p=0.002). The total number of LN+ (HR=1.1; 95% CI 1.01-1.2, p=0.04) and Gleason 8-10 (HR=1.96; 95% CI 1.1-3.4, p=0.02) were predictors of BCR on multivariate analysis.
Level of Study	4
Reference	3. Muck A, Langesberg C, Mugler M, Rahnenführer J, Wullich B, Schafhauser W. Clinical outcome of patients with lymph node-positive prostate cancer following radical prostatectomy and extended sentinel lymph node dissection. Urol Int. 2015;94(3):296-306
Study type	longitudinal observational study
Patients	819 patients with clinically localized PCa, confirmed by biopsy, were treated with RRP plus eSLND
Purpose of Study	evaluate the clinical outcome after extended sentinel lymph node dissection (eSLND) and radical retropubic prostatectomy (RRP) in patients with clinically localized prostate cancer (PCa)
Study Results	The mean follow-up was 5.3 years. Lymph node (LN) metastases occurred in 140 patients. We removed an average of 10.9 LNs via eSLND from patients with pN1 PCa. Postoperatively, 121 pN1 patients temporarily received adjuvant androgen deprivation therapy. The mean survival periods for RFS, RFS after secondary treatment, CSS, and OS were 4.7, 7.0, 8.8, and 8.1 years, respectively. The cancer-specific death rate of the 140 pN1 patients was 13.6%. RFS, CSS, and OS were significantly correlated with pathological margin status, LN density, the total diameter of evident metastases, and membership in the subgroup ‘micrometastases only’.
Level of Study	4
Reference	4. Moschini M, Fossati N, Abdollah F, Gandaglia G, Cucchiara V, Dell’Oglio P, Luzzago S, Shariat SF, Dehò F, Salonia A, Montorsi F, Briganti A. Determinants of long-term survival of patients with locally advanced prostate cancer: the role of extensive pelvic lymph node dissection. Prostate Cancer Prostatic Dis 2016;19(1):63-7.
Study type	longitudinal observational study
Patients	1,586 pT3-T4 PCa patients treated with RP and extended PLND between 1987 and 2012
Purpose of Study	Assessing the impact of more extensive PLND on cancer-specific mortality (CSM) in patients treated with surgery for locally advanced PCa.
Study Results	The average number of nodes removed was 19 (median: 17; interquartile range: 1123). Mean and median follow-up were 80 and 72 months, respectively. At multivariable analyses, Gleason score 8-10 (hazard ratio (HR): 2.5) and a higher number of positive nodes (HR: 1.06) were independently associated with higher CSM rate (all P<0.05). Conversely, higher number of removed LNs (HR: 0.94) and adjuvant radiotherapy (HR: 0.54) were independent predictors of lower CSM rates (all P≤0.03).
Level of Study	4
Reference	5. Fossati N, Willemse PM, Van den Broeck T, van den Bergh RCN, Yuan CY, Briers E, Bellmunt J, Bolla M, Cornford P, De Santis M, MacPepple E, Henry AM, Mason MD, Matveev VB, van der Poel HG, van der Kwast TH, Rouvière O, Schoots IG, Wiegel T, Lam TB, Mottet N, Joniau S. The Benefits and Harms of Different Extents of Lymph Node Dissection During Radical Prostatectomy for Prostate Cancer: A Systematic Review. Eur Urol 2017;72(1):84-109.
Study type	Systematic Review
Patients	29 studies were included. Specifically, 21 studies (15 full-text articles and six conference abstracts) compared no PLND versus any form of PLND, whereas eight studies (four fulltext articles and four conference abstracts) compared lPLND or sPLND versus ePLND or sePLND.
Purpose of Study	To systematically review the relevant literature assessing the relative benefits and harms of PLND for oncological and non-oncological outcomes in patients undergoing radical prostatectomy for PCa.
Study Results	Overall, 66 studies recruiting a total of 275,269 patients were included (44 full-text articles and 22 conference abstracts). Oncological outcomes were addressed by 29 studies, one of which was a randomized clinical trial (RCT). Non-oncological outcomes were addressed by 43 studies, three of which were RCTs. There were high risks of bias and confounding in most studies. Conflicting results emerged when comparing biochemical and clinical recurrence, while no significant differences were observed among groups for survival. Conversely, the majority of studies showed that the more extensive the PLND, the greater the adverse outcomes in terms of operating time, blood loss, length of stay, and  postoperative complications. No significant differences were observed in terms of urinary continence and erectile function recovery.
Level of Study	1
Reference	6. Narita T, Koie T, Ookubo T, Mitsuzuka K, Narita S, Yamamoto H, Inoue T, Hatakeyama S, Kawamura S, Tochigi T, Habuchi T, Arai Y, Ohyama C. The impact of extended lymph node dissection versus neoadjuvant therapy with limited lymph node dissection on biochemical recurrence in high-risk prostate cancer patients treated with radical prostatectomy: a multiinstitutional analysis. Med Oncol 2017;34(1):1.
Study Results	Multicenter non-randomized longitudinal observational Study
Patients	2,403 consecutive Pca patients treated with RP
Purpose of Study	To assess whether e-PLND confers an oncological benefit for high-risk Pca compared to neoadjuvant luteinizing hormone-releasing hormone and estramustine (LHRH + EMP)
Study Results	In the e-PLND group, we identified 238 high-risk Pca patients who underwent RP and e-PLND, with lymphatic tissue removal around the obturator and the external iliac regions, and hypogastric lymph node dissection. The neoadjuvant therapy with limited PLND (l-PLND) group included 280 high-risk Pca patients who underwent RP and removal of the obturator node chain between September 2005 and June 2014 at Hirosaki University. The outcome measure was BRFS. The 5-year biochemical recurrence-free survival rates for the neoadjuvant therapy with l-PLND group and e-PLND group were 84.9 and 54.7%, respectively (P<0.0001). The operative time was significantly longer in the e-PLND group compared to that of the neoadjuvant therapy with l-PLND group. Grade 3/4 surgeryrelated complications were not identified in both groups.
Level of Study	4

 

KQ 14. 고위험도 전립선암 환자에서 근치적전립선 절제술 후 병리학적으로 불량한 예후를 보였을 때 술 후 보조적 방사선 치료(adjuvant RTX)는 구제 방사선 치료(salvage RTX)보다 생존율이 높은가? 

권고사항	권고수준	근거수준
고위험도 전립선암 환자에서 근치적 전립선 절제술 후 병리학적으로 불량한 예후를 보였을 때 술 후 보조적 방사선 치료(adjuvant RTx)와 구제 방사선 치료(salvage RTx)를 시행하는 것은 두 가지 치료법 사이에 생존율에 차이가 없으므로, 이와 같은 상황에서 보조적 방사선 치료(adjuvant RTx) 및 구제 방사선 치료(salvage RTx) 모두 고려할 수 있다.	A	I

 개요

근치적 전립선 절제술은 국소 전립선암의 표준적인 치료 중 하나로서 훌륭한 장기 추적 결과를 보여준다. 그러나 정낭침범, 피막외확대 침범, 임파선 전이 등의 불량한 병리학적 결과를 보이는 환자들은 수술적 치료 단독요법으로는 장기간 추적관찰 시 재발의 가능성이 높아지고 생존율이 저하될 수 있다. 따라서 방사선 치료를 포함한 여러 추가 방법을 고려해야 한다. 보조적 방사선 치료(adjuvant radiotherapy)는 재발의 증거가 없는 상태에서 수술 후 1-6개월 사이에 시행하는 방사선 치료로서 전 립선와(prostate bed)를 기본으로 정낭와(seminal vesicle bed)나 골반 임파선을 포함하기도 한다^[1-4].

기존 가이드라인 요약 및 수용성, 적용성 평가

고위험도 전립선암 환자에 대한 세 가지 전향적 무작위 연구에서 보조적 방사선 치료가 관찰군에 비해 생화학 재발률(biochemical recurrence)을 낮춘다고 보고되었다. 먼저 EORTC trial 229111에서는 pT2-3N0R1 환자 1,005명을 관찰군(wait-and-see policy; n=503)과 보조방사선치료군 (postoperative irradiation, 60 Gy; n=502)으로 무작위 배정 후 중간추적 기간 10.6년(2개월-16.6년)동안 추적하였다. 70세 이하 환자들에서 보조방사선치료군 502명 중 198명(39.4%)에서 생화학적/ 임상적 재발 또는 사망이 발생한 반면 관찰군 503명 중 311명(61.8%)에서 생화학적/임상적 재발 또 는 사망이 발생하여, 보조방사선치료는 10년 생화학적 무진행 생존율(biochemical progression-free survival)을 유의하게 낮추었다(HR 0.49 [95% CI 0.41-0.59]; p<0.0001). 국소 재발 또한 보조적 방사선 치료군이 관찰군보다 더 우수하였다. 그러나 전체 생존율(Overall survival)은 보조적 방사선 치료군에서 관찰군보다 유의한 증가를 보여주지 못했다. Grade 4 독성(toxicity)은 두 군에서 관찰되지 않았으며 후기 부작용은 보조적 방사선 치료군에서 더 빈번하였다(10년 누적 발생률 70.8 vs 59.7%; p=0.001). ARO trial[2]은 pT3N0이고 수술 후 PSA <0.1 ng/mL에 도달환 환자 385명을 관찰군(중간 추적기간 113개월)과 보조방사선치료군(60 Gy, 중간추적기간 111개월)으로 무작위 배정하여 진행한 연구이다. 10년 무진행 생존율(progression-free survival)은 보조방사선치료군 56%, 관찰군 35%였으 며(p<0.0001) 특히 관찰군 중 pT3b와 절제면 양성 환자들의 무진행 생존율은 각각 28%와 27%로 더욱 감소하였다. 그러나 무전이 생존율(Metastasis-free survival)이나 전체 생존율은 보조적 방사선 치료군에서 관찰군보다 유의한 증가를 보여주지 못했다. SWOG 8794 trial^[3]에서는 pT3N0M0 431명의 환자를 보조방사선치료군(60-64 Gy; n=214)과 관찰군(n=211)으로 무작위 배정하였다. 보조방사선치료는 10년 무전이 생존율을 유의하게 증가시켰고(보조방사선치료군 71% vs 관찰군 61%, 중간 생존 연장기간 1.8년; p=0.016) 10년 전체 생존율 또한 보조적 방사선 치료군에서 유의하게 증가하였다(보조방사선치료군 74% vs 관찰군 66%, 중간 생존 연장기간 1.9년; p=0.023).

불량한 병리학적 결과를 보인 환자 중 추가 치료를 시행하지 않은 환자의 50%에서 재발이 관찰되지 않았다는 보고도 있다^[6,7]. 이런 환자들에게 보조적 방사선 치료를 시행하는 것은 단기간 및 장기간 부작용, 방사선 치료 비용, 치료 기간 등을 고려할 때 과잉치료일 수 있으므로 미국에서는 보조적 방사선 치료가 약 20% 미만의 환자에게만 시행되고 있다^[8]. pT3N0 환자들을 대상으로 보조 방사선 치료와 조기 구제 방사선 치료의 효과를 비교한 가장 대규모의 후향적 연구에서 2년 생화학적 무재발 생존율이 보조 방사선 치료군에서 91%, 5년 생화학적 무재발 생존율이 78%였고, 구제 방사선 치료 군에서 2년 생화학적 무재발 생존율이 93%, 5년 생화학적 무재발 생존율이 82%로 두 군 간 차이를 보이지 않았다. 이러한 결과로 저자들은 구제 방사선 치료가 과다치료를 줄이면서도 종양학적 성적을 유지할 수 있는 방법이라고 결론내렸다^[9]. 그러므로 고위험도 전립선암 환자에서 수술적 치료 후 즉각적인 보조적 방사선 치료를 시행하지 않고 생화학적 재발이 확인되었을 시에 시행하는 구제 방사선 치료가 무작위 전향적 연구 결과가 빈약함에도 불구하고 옵션이 될 수 있다^[8].

이러한 연구 결과들을 토대로, 2015년 대한비뇨기종양학회 전립선암 진료지침에서는 불량한 병리학적 결과 즉 pT3, 수술절제면 양성, Gleason 점수 8-10, 정낭 침범 등이 보조 방사선 치료의 적응증이 될 수 있으며 전반적인 종양학적 결과를 향상시킬 수 있다고 기술하였다(근거수준: 1b). 또한 2016 유럽비뇨기과학회 가이드라인에서는 PSA가 측정되지 않을 정도로 감소한 pT3N0M0환자에서 도 최소한 생화학적 재발률은 낮출 수 있으므로 보조적 방사선 치료 요법을 환자에게 설명하라고 권 고하였다(근거수준: 1a). 한편 2014 NICE (National Collaborating Centre for Cancer) 전립선암 가 이드라인에서는 절제면 양성 환자에서 보조적 방사선 치료가 생화학적 재발률은 낮추지만 전반적인 생존율(overall survival) 및 질환 특이 생존율(disease specific survival)은 낮추지 못하기 때문에^[6,7] 방 사선 치료의 부작용을 고려하여 보조적 방사선 치료를 실시하지 말라는 의견도 제시했다.

KQ 14. 고위험도 전립선암 환자에서 근치적전립선 절제술 후 병리학적으로 불량한 예후를 보였을 때 술 후 보조적 방사 선 치료(adjuvant RTx)는 구제 방사선 치료(salvage RTx)보다 생존율이 높은가?
지침(제목)	권고	권고등급	근거수준	page
1. 2015 KUOS	수술 후 불량한 병리학적 결과가 보고되었을 때(정낭침범, 피막외확대침범, 수술가장자리양성등) 수술후보조방사선치 료(adjuvant radiotherapy)를 시행하여 전반적인 종양학적 결과를 향상시킬 수 있다 [1-3] .	제시안함	1b	28
2. EAU 2016	In patients with pT3N0M0 PCa and an undetectable PSA following RP, discuss adjuvant EBRT because it improves at least biochemical-free survival [1-3] .	A	1a	48
6. NICE 2014	Do not offer immediate postoperative radiotherapy after radical prostatectomy, even to men with margin- positive disease, other than in the context of a clinical trial [5,6] .	제시안함	제시안함	280
9. CCAACN 2010	It is recommended that patients with extracapsular extension, seminal vesicle involvement or positive surgical margins receive postoperative EBRT within four months of progression [1-3] .	B	II	56

지침(제목)		1. 2015 KUOS	2. EAU 2016	6. NICE 2014	9. CCAACN 2010
수용성	인구 집단(유병률, 발생률 등)이 유사하다.	예	아니오	아니오	아니오
	가치와 선호도가 유사하다.	예	예	아니오	예
	권고로 인한 이득은 유사하다	예	예	아니오	예
	해당 권고는 수용 할 만하다.	예	예	아니오	예
적용성	해당 중재/장비는 이용 가능하다.	예	예	예	예
	필수적인 전문기술이 이용 가능하다.	예	예	예	예
	법률적/제도적 장벽이 없다.	예	예	예	예
	해당 권고는 적용 할 만하다.	예	예	아니오	예

네 가지 가이드라인 중 NICE 2014의 권고사항은 차이를 보인다. 수용성 및 적용성에서 국내 가이드라인 및 다른 외국 가이드라인과 차이를 보여 배제하였다. 

업데이트 근거 요약

고위험 전립선암 환자에서 근치적 전립선절제술 후 절제면 양성, 전립선 피막 침범(extra prostatic extension, pT3) 및 정낭침범 등 병리학적 불량 예후인자가 있는 경우 보조적 방사선치료는 생존율 향상에 도움이 되는지 여부는 논란이 있지만 관찰군과 비교해 볼 때 생화학적 재발률을 낮추는 것은 확실하다^[1-3]. 반면 재발이 의심될 때 시행하는 구제 방사선 치료 또한 종양 치료 효용이 후향적 연구에서 보고되었다^[9]. Hsu 등은 보조적 방사선 치료와 구제 방사선 치료의 효과를 74개월 동안 추적 관찰한 연구에서 PSA가 1.0 ng/mL 미만인 경우 조기 구제 방사선 치료는 보조적 방사선 치료와 무전이 생존/전반적 생존에서 비슷한 치료 효과를 보이나 PSA가 1.0 ng/mL 초과인 경우 지연 구제 방사선 치료는 그 성적이 그리 좋지 않음을 보고하였다^[10]. 고위험 환자에서 수술 후 보조적 방사선치료와 구제 방사선치료(salvage radiotherapy)의 효과를 비교한 전향적 연구는 현재까지 보고되지 않은 상태이나 후향적 연구에서 전이 및 전반적 생존에 대한 두 가지 방법의 치료 효과는 큰 차이가 없는 것으로 나왔고^[8,11,12] 현재 다양한 무작위 연구가 진행 중이다^[13-15]. 이 연구 결과들이 나오면 고위험도 전립선 암 환자에서 근치적 전립선 절제술 후 병리학적으로 불량한 예후를 보였을 때 술 후 보조적 방사선 치료(adjuvant RTx)와 구제 방사선 치료(salvage RTx) 중 어떠한 치료법이 생존율을 높일 수 있을 지 확실해 질 수 있을 것이다^[16,17].

술 후 즉각적인 보조 방사선 요법과 관련하여 방사선 요법의 단기(15-35%) 및 장기적인 부작용(2-8%)도 반드시 고려해야 한다^[8,18]. 술 후 보조적 방사선 치료와 구제 방사선 치료 방침을 정할 때 개별 환자의 임상적, 병리학적 특징을 고려한 정확한 환자 선택이 매우 중요하다^[16,17].

참고문헌

1. Bolla M, van Poppel H, Tombal B, et al. Postoperative radiotherapy after radical prostatectomy for high risk prostate cancer: long-term results of a randomised controlled trial (EORTC trial 22911). Lancet 2012:380:2018-27.

2. Wiegel T, Bartkowiak D, Bottke D, et al. Adjuvant radiotherapy versus wait-and-see after radical prostatectomy: 10-year follow-up of the ARO 96-02/AUO AP 09/95 trial. Eur Urol 2014;66:243-50.

3. Thompson IM, Tangen CM, Paradelo J, et al. Adjuvant radiotherapy for pathological T3NOMO prostate cancer significantly reduces risk of metastases and improves survival: long-term followup of a randomized clinical trial. J Urol 2009:181:956-62.

4. Gandaglia G, Cozzarini C, Mottrie A, et al. The Role of Radiotherapy After Radical Prostatectomy in Patients with Prostate cancer. Curr Oncol Rep 2015:17:53. 5. Mottet N, Bellmunt J, Bolla M, et al. EAU-ESTRO-SIOG Guidelines on Prostate cancer. Part 1: Screening, Diagnosis, and Local Treatment with Curative Intent. Eur Urol 2017:71:618-29. 6. Bolla M, van Poppel H, Collette L, et al. Postoperative radiotherapy after radical prostatectomy: a randomised controlled trial (EORTC trial 22911). Lancet 2005;366:572-8.

7. Thompson IM, Jr., Tangen CM, Paradelo J, et al. Adjuvant radiotherapy for pathologically advanced prostate cancer: a randomized clinical trial. JAMA 2006:296:2329-35.

8. Mishra MV, Scher ED, Andrel J, et al. Adjuvant versus salvage radiation therapy for prostate cancer patients with adverse pathologic features: comparative analysis of long-term outcomes. Am J Clin Oncol 2015:38:55 60.

9. Briganti A, Wiegel T, Joniau S, et al. Early Salvage Radiation Therapy Does Not Compromise Cancer Control in Patients with PT3NO Prostate cancer After Radical Prostatectomy: Results of a Match-controlled Multi institutional Analysis. European Urology:62:472-87.

10. Hsu CC, Paciorek AT, Cooperberg MR, Roach M, 3rd, Hsu C, Carroll PR. Postoperative radiation therapy for patients at high-risk of recurrence after radical prostatectomy: does timing matter? BJU Int 2015:116:713 20.

11. Fossati N, Karnes RJ, Boorjian SA, et al. Long-term Impact of Adjuvant Versus Early Salvage Radiation Therapy in PT3NO Prostate Cancer Patients Treated with Radical Prostatectomy: Results from a Multi-institutional Series. Eur Urol 2017:71:886-93.

12. Chen B-H, Cha T-L, kao C-C, et al. Results of early or delayed adjuvant radiotherapy for prostate cancer with adverse pathological tumor characteristics: A single-institute experience. Urological Science 2015:26:235-7. 13. Parker C, Clarke N, Logue J, et al. RADICALS (Radiotherapy and Androgen Deprivation in combination after Local Surgery). Clin Oncol (R Coll Radiol) 2007:19:167-71.

14. Parker C, Sydes MR, Catton C, et al. Radiotherapy and androgen deprivation in combination after local surgery (RADICALS): a new Medical Research Council/National Cancer Institute of Canada phase III trial of adjuvant treatment after radical prostatectomy. BJU Int 2007:99:1376-9.

15. Pearse M, Fraser-Browne C, Davis ID, et al. A Phase III trial to investigate the timing of radiotherapy for prostate cancer with high-risk features: background and rationale of the Radiotherapy -- Adjuvant Versus Early Salvage (RAVES) trial. BJU Int 2014;113 Suppl 2:7-12.

16. Gandaglia G, Briganti A, Clarke N, et al. Adjuvant and Salvage Radiotherapy after Radical Prostatectomy in Prostate Cancer Patients. Eur Urol 2017:72:689-709.

17. van der Poel H, van Stam MA. Early or delayed radiotherapy after prostatectomy-who really benefits? Transl Androl Urol 2017:6:593-4.

18. Hegarty SE, Hyslop T, Dicker AP, Showalter TN. Radiation Therapy after Radical Prostatectomy for Prostate Cancer: Evaluation of Complications and Influence of Radiation Timing on Outcomes in a Large, Population Based Cohort. PLoS One 2015:10. 

근거표

KQ14
Reference	1. Mishra MV, Scher ED, Andrel J, et al. Adjuvant versus salvage radiation therapy for prostate cancer patients with adverse pathologic features: comparative analysis of longterm outcomes. Am J Clin Oncol 2015;38:55-60[8].
Study type	Compative study
Patients	186 patients treated with postprostatectomy radiation therapy with pT3 tumors, or pT2 with positive surgical margins
Purpose of Study	To compare long-term outcomes of men with adverse pathologic features after adjuvant radiation therapy (ART) versus salvage radiation therapy (SRT) after radical prostatectomy at our institution.
Study Results	Cumulative freedom from biochemical failure (FFBF), freedom from metastatic failure (FFMF), and overall survival rates were estimated utilizing the Kaplan-Meier method. Multivariate analyses were performed to determine independent prognostic factors correlated with study endpoints. Propensity score analyses were performed to adjust for confounding because of nonrandom treatment allocation. RESULTS: A total of 186 patients with adverse pathologic features treated with ART or SRT were identified. The median follow-up time after radical prostatectomy was 103 and 88 months after completion of radiation therapy. The Kaplan-Meier estimates for 10-year FFBF was 73% and 41% after ART and SRT, respectively (log-rank, P=0.0001). Ten-year FFMF was higher for patients who received ART versus SRT (98.6% vs. 80.9%, P=0.0028). On multivariate analyses there was no significant difference with respect to treatment group in terms of FFBF, FFMF, and overall survival after adjusting for propensity score. CONCLUSIONS: Although unadjusted analyses showed improved FFBF with ART, the propensity scoreadjusted analyses demonstrated that long-term outcomes of patients treated with ART  and SRT do not differ significantly. These results, with decreased effect size of ART after adjusting for propensity score, demonstrate the potential impact of confounding on observational research.
Level of Study	3
Reference	2. Gandaglia G, Cozzarini C, Mottrie A, et al. The Role of Radiotherapy After Radical Prostatectomy in Patients with Prostate Cancer. Curr Oncol Rep 2015;17:53[4].
Study type	Review article
Patients	1,005 patients (wait-and-see policy [n=503] or postoperative irradiation [n=502])
Purpose of Study	To report the long-term results of a trial of immediate postoperative irradiation versus a wait-and-see policy in patients with prostate cancer extending beyond the prostate
Study Results	Bolla et al. evaluated 1005 patients with pT3 or pT2R1 pN0 PCa treated with RP included in the European Organisation for Research and Treatment of Cancer (EORTC) trial 22911. Patients were randomized to wait-and-see vs. immediate irradiation after surgery. The authors demonstrated that at a median follow-up of 127 months, immediate RT significantly improved BCR-free survival and local control rates as compared to initial observation. Additionally, post-operative irradiation improved clinical progression-free survival in men younger than 70 years and in patients with positive margins. However, no benefit from adjuvant RT was found in terms of metastasis-free and cancer-specific survival.
Level of Study	1
Reference	3. Hsu CC, Paciorek AT, Cooperberg MR et al. Postoperative radiation therapy for patients at high-risk of recurrence after radical prostatectomy: does timing matter? BJU Int 2015;116(5):713-20[10].
Study type	Multicenter longitudinal observational study
Patients	6,176 (CaPSURE)
Purpose of Study	To evaluate among radical prostatectomy (RP) patients at high-risk of recurrence whether the timing of postoperative radiation therapy (RT) (adjuvant, early salvage with detectable post-RP prostate-specific antigen [PSA], or ‘late’ salvage with a PSA level of >1.0 ng/mL) is significantly associated with overall survival (OS), prostate-cancer specific survival or metastasis-free survival, in a longitudinal cohort.
Study Results	After a median of 74 months after RP, 65 men had died (with 37 events of PCSMM). Adjuvant and salvage RT patients had comparable high-risk features. Compared with adjuvant, salvage RT (early or late) had an increased association with all-cause mortality (hazard ratio [HR] 2.7, P=0.018) and with PCSMM (HR 4.0, P=0.015). PCSMM-free survival differed by further stratification of timing, with 10-year estimates of 88%, 84%, and 71% for adjuvant, early salvage, and late salvage RT, respectively (P=0.026). For PCSMM-free survival and OS, compared with adjuvant RT, late salvage RT had statistically significantly increased risk; however, early salvage RT did not. This analysis suggests that patients who underwent early salvage RT with PSA levels of <1.0 ng/mL may have comparable metastasis-free survival and OS compared with adjuvant RT; however, late salvage RT with a PSA level of >1.0 ng/mL is associated with worse clinical outcomes.
Level of Study	2
Reference	4. Chen B-H, Cha T-L, Kao C-C, et al. Results of early or delayed adjuvant radiotherapy for prostate cancer with adverse pathological tumor characteristics: A single-institute experience. Urological Science 2015;26:235-7[12].
Study type	Single-center longitudinal observational study
Patients	53
Purpose of Study	We present a retrospective study of adjuvant radiotherapy (ART) in adverse pathological tumor characteristics of PCa, and analyze the optimal time for ART.
Study Results	There was no PCa-specific mortality in the 5-year follow-up. When compared with the delayed ART in men with adverse pathological characteristics of PCa, early ART was associated with the trend to improve the 5-year BCFS (89% vs. 73%; p=0.1) and less salvage hormonal therapy (45% vs. 54%; p=0.29). The delayed ART is associated with the trend of fewer urethral strictures (9% vs. 14%; p=0.32). But, there was no significant difference between both groups.
Level of Study	4
Reference	5. Fossati N, Karnes RJ, Boorjian SA, et al. Long-term Impact of Adjuvant Versus Early Salvage Radiation Therapy in pT3N0 Prostate Cancer Patients Treated with Radical Prostatectomy: Results from a Multi-institutional Series. Eur Urol 2017;71:886-93[11].
Study type	Multicenter longitudinal observational study
Patients	510
Purpose of Study	To test the hypothesis that aRT was associated with better cancer control and survival compared with observation followed by esRT.
Study Results	Overall, 243 patients (48%) underwent aRT, and 267 (52%) underwent initial observation. Within the latter group, 141 patients experienced PSA relapse and received esRT. Median follow-up after RP was 94 mo (interquartile range [IQR]: 53-126) and 92 mo (IQR: 70-136), respectively (p=0.2). MFS (92% vs 91%; p=0.9) and OS (89% vs 92%; p=0.9) at 8 yr after surgery were not significantly different between the two groups. These results were confirmed in multivariable analysis, in which observation followed by esRT was not associated with a significantly higher risk of distant metastasis (hazard ratio [HR]: 1.35; p=0.4) and overall mortality (HR: 1.39; p=0.4) compared with aRT. Using the nonparametric curve fitting method, a comparable proportion of MFS and OS at 8 yr among groups was observed regardless of pathologic cancer features (p=0.9 and p=0.7, respectively). Limitations consisted of the retrospective nature of the study and the relatively small size of the patient population.
Level of Study	2
Reference	6. Gandaglia G, Briganti A, Clarke N, et al. Adjuvant and Salvage Radiotherapy after Radical Prostatectomy in Prostate Cancer Patients. Eur Urol 2017;72:689-709[16].
Study Results	Systematic review
Patients	70 studies
Purpose of Study	To analyze the role of postoperative radiotherapy (RT) in patients with aggressive PCa
Study Results	Three randomized trials demonstrated that immediate RT after RP reduces the risk of recurrence in patients with aggressive PCa. However, immediate postoperative RT is associated with an increased risk of acute and late side effects ranging from 15% to 35% and 2% to 8%, respectively. Retrospective studies support the oncologic efficacy of initial observation followed by salvage RT administered at the first sign of recurrence; however, the impact of this delay on long-term control remains uncertain. Hopefully, ongoing randomized trials will shed light on the role of adjuvant RT versus observation ± salvage RT in individuals with adverse features at RP. Accurate patient selection based on clinical characteristics and molecular profile is crucial. Dose escalation, whole-pelvis RT, novel techniques, and the use of hormonal therapy might improve the outcomes of postoperative RT. Immediate RT reduces the risk of recurrence after RP in patients with aggressive disease. However, this approach is associated with an increase in the incidence of short- and long-term side effects. Observation followed by salvage RT administered at the first sign of recurrence might be associated with durable cancer control, but prospective randomized comparison with adjuvant RT is still awaited. Dose escalation, refinements in the technique, and the concomitant use of hormonal therapies might improve outcomes of patients undergoing postoperative RT.
Level of Study	1

 

KO 15. 고위험 전립선암 환자에서 능동적 감시는 근치적 전립선절제술에 비해 생존율이 낮은가?

권고사항	권고수준	근거수준
고위험 전립선암 환자에서 근치적 전립선 절제술을 시행하는 것이 능동적 감시보다 생존율을 향상시키므로 근치적 전립선 절제술을 시행하는 것을 권고 한다.	B	II

개요

능동적 감시는 전립선암의 경과를 적극적으로 추적 관찰하면서 적절한 시기에 전립선 절제술이나 방사선 치료 등 근치적인 치료를 시행하는 것이다(NCCN Guidelines Version 3.2016). 일부의 전립선암은 환자의 기대여명에 영향을 끼치지 않으며 치료로 인한 합병증 및 사회적인 치료 비용의 증가도 문제가 되고 있다. 따라서 능동적 감시는 전립선암의 과다 치료에 의한 의료비용의 감소 또는 환자의 삶의 질을 보존하기 위해 시행되며 이를 위해 추적 관찰 중 적절한 시점에 적극적 치료로 변경하는 것이 필요하다. 또한 능동적 감시는 신중하게 선택된 저위험군 환자에게만 적용되어야 한다(EAUESTRO-SIOG Guidelines on Prostate Cancer, 2016).

현재로서는 고위험군의 전립선암 환자에서 능동적 감시와 근치적 절제술을 시행한 결과를 직접적으로 비교한 연구는 그리 많지 않은 상황이다. Bill-Axelson 등은 전립선암 환자를 근치적 절제술군과 감시 관찰군으로 무작위 배정하여 18년간 관찰한 전향적 연구를 보고하였다. 이 중 고위험군 환자의 경우 근치적 전립선 절제술을 시행하여도 감시 관찰을 시행한 고위험 환자군에 비해 전체 사망률, 암-특이 사망률, 원격 전이의 위험을 감소시키지 못하는 것으로 나타나 고위험 환자군에서도 능동적 감시가 유효할 것을 시사하였다^[1].

하지만 이에 반대되는 연구들이 보고되어 있는데 미국의 Tewari 등은 고위험도 전립선암 환자 453명을 대상으로 보존적 치료, 근치적 방사선 치료, 근치적 전립선 절제술을 시행하고 관찰한 연구결과를 발표하였다. 이 연구에서 전체 생존기간의 중앙값은 5.2, 6.7, 9.7년으로 보존적 치료에서 가장 낮았고 근치적 전립선 절제술 시행군에서 가장 높았다. 암 특이 생존기간의 중앙값도 보존적 치료에서는 7.8년으로 낮았으며 방사선치료와 근치적 전립선 절제술 군에서 14년 이상으로 더욱 좋은 결과를 보였다^[2].

또한 2012년에 Wilt 등이 발표한 PIVOT 연구에서는 전립선암 환자를 무작위로 감시 관찰군과 근치적 전립선 절제술 두 군으로 나누어 10년 이상 관찰한 결과를 발표하였다^[3]. 이 연구에서 고위험 도 전립선 환자군에서는 근치적 전립선 절제를 시행할 경우 감시 관찰하는 경우보다 전체 사망률이 6.7% 감소되는 것으로 나타났으나 통계적으로 유의한 차이를 보이지는 못하였지만 근치적 전립선 절제술을 시행한 PSA 10 ng/mL 초과 또는 중간위험도 이상의 환자에서 암 특이 사망률이 감시 관찰 시행군에 비해 9-11% 유의하게 감소하는 결과가 나타나 고위험도 전립선암 환자에서 근치적 전립선 절제술 시행이 종양학적 성적을 높일 수 있음을 보였다. 이러한 연구결과를 바탕으로 기존의 국내 및 해외 가이드라인에서 고위험 전립선암 환자에 대해 능동적 감시를 권고하지 않고 있다.

기존 가이드라인 요약 및 수용성, 적용성 평가

2015 KUOS 전립선암 진료지침에서는 고위험군 이상의 전립선암 환자에서 선택적으로 근치적 전립선 절제술이 유용할 수 있다고 하였고 2007년 미국비뇨의학과학회 진료지침에서는 근치적 전립선 절제술은 전립선암의 재발율을 낮추고 생존율을 향상시킨다고 하였다. 2014년 NICE 진료지침에서는 고위험 국소 전립선암 환자들에게 능동적 감시를 시행하지 말 것을 권고하고 있다. 2016년 유럽비뇨의학과학회 진료지침에서는 기대여명이 10명 초과인 고위험/국소 진행성 전립선암 환자들에게 전립선절제술을 비롯한 복합 치료를 시행할 것을 권고하는 반면 수술이나 방사선 치료 등을 시행할 수 없는 환자나 기대 여명이 짧은 고위험 국소 전립선암 환자들에게는 주의 깊은 관찰을 시행하는 것을 권고하고 있다. 요약하면 고위험 전립선암 환자에서 근치적 전립선 절제술을 시행하는 것이 능동적 감시보다 재발의 위험을 낮추고 생존율을 향상시키므로 근치적 전립선 절제술을 시행하는 것을 권고한다.

KQ 15. 고위험 전립선암 환자에서 능동적 감시는 근치적 전립선절제술에 비해 생존율이 낮은가?
지침(제목)	권고	권고등급	근거수준	page
1. 2015 KUOS	고위험도군 이상의 전립선암 환자에서도 선택적으로 근치적 전립선절제술이 유용할 수 있는데, 혈청전립선특이항원 10 ng/ml 이상, 임상적 병기T2b 이상, Gleason score 9 이상, 고위험 등급 암의 코어 수가 더 많음, 또는 코어의 50% 이 상 암이 침범함 등의 인자를 고려하여 근치적 전립선절제술 시행을 결정할 수 있다	제시안함	2b	36
2. EAU 2016	High risk localised: Offer watchful waiting to patients not eligible for local curative treatment and those with a short life expectancy.	제시안함	제시안함	71
3. AUA 2007	High-risk patients who are considering specific treatment options should be informed of findings of recent high-quality clinical trials, including that: When compared with watchful waiting, radical prostatectomy may lower the risk of cancer recurrence and improve survival; and For those considering external beam radiotherapy, use of hormonal therapy combined with conventional radiotherapy may prolong survival	standard:	제시안함	31
6. NICE 2014	Do not offer active surveillance to men with high-risk localised prostate cancer.	제시안함	제시안함	166

지침(제목)		1. 2015 KUOS	2. EAU 2016	3. AUA 2007	5. NICE 2014
수용성	인구 집단(유병률, 발생률 등)이 유사하다.	예	아니오	아니오	아니오
	가치와 선호도가 유사하다.	예	예	예	예
	권고로 인한 이득은 유사하다	예	예	예	예
	해당 권고는 수용 할 만하다.	예	예	예	예
적용성	해당 중재/장비는 이용 가능하다.	예	예	예	예
	필수적인 전문기술이 이용 가능하다.	예	예	예	예
	법률적/제도적 장벽이 없다.	예	예	예	예
	해당 권고는 적용 할 만하다.	예	예	예	예

업데이트 근거 요약

2015년에 Lei 등은 고위험 전립선암 환자에서의 첫번째 치료 옵션에 대한 체계적 문헌 고찰을 시행하여 근치적 전립선절제술, 방사선치료, 근접치료, 호르몬치료, 관찰 요법 등의 장기간 생존 성적을 비교하였다. 치료 성적은 근치적 전립선절제술과 남성 호르몬 억제 요법을 동반한 방사선치료가 가장 좋은 것으로 밝혀졌고 방사선치료 단독 요법, 남성 호르몬 억제 요법 및 관찰의 순서로 치료 성적이 좋았다. 전체 생존율은 근치적 전립선절제술 군에서 의미있게 높았으며 암 특이 사망률은 가장 낮았다. 관찰 요법은 가장 나쁜 결과를 보여주었다^[4].

Johnston 등은 2017년에 European urology에 ProtecT 연구에서 탈락한 임상병기 T3-4 또는 PSA>20 이상의 국소 진행성이거나 국소/원격 전이 전립선암 환자를 대상으로 중앙값 7.4년간 추적 관찰한 연구 결과를 발표하였다^[5]. 이 연구에서 능동적 감시 또는 대기관찰을 시행한 환자군과의 단독 비교는 이루어지지 않았으나 일차적 호르몬 치료를 받았거나 완화 항암화학요법, 관찰 등을 시행한 환자들을 비근치적 치료군으로 묶어 근치적 전립선 절제술군 및 근치적 방사선 치료군과 결과를 비교 하였다. 근치적 전립선 절제술 시행군은 근치적 방사선 치료군에 비해 유의하지는 않지만 전체 생존율과 암 특이 생존율이 높았고 비근치적 치료 시행군보다 유의하게 전체 생존율과 암 특이 생존율이 높았다.

기존의 가이드라인에 이미 고위험 환자군에서 능동적 감시가 적절하지 않음이 반영되어 있고^[3] 고위험 환자군에서 일차치료로 근치적 전립선 절제술이나 근치적 방사선 치료가 보존적 치료나 능동적 감시보다 우월함을 암시하는 증거들이 추가되고 있다. 이를 바탕으로 고위험 전립선암 환자에 대해서는 능동적 감시보다 근치적 치료를 시행하는 것이 필요할 것으로 보인다.

참고문헌

1. Bill-Axelson A, Holmberg L, Garmo H, et al. Radical Prostatectomy or Watchful Waiting in Early Prostate Cancer. N Engl J Med 2014:370(10):932-42.

2. Tewari A, Divine G, Chang P, et al. Long-Term Survival in Men With High Grade Prostate Cancer: A Comparison Between Conservative Treatment, Radiation Therapy and Radical Prostatectomy-A Propensity Scoring Approach. J Urol 2007:177(3):911-5..

3. Wilt TJ, Brawer MK, Jones KM, et al. Radical prostatectomy versus observation for localized prostate cancer. | N Engl J Med 2012:367(3):203-13.

4. Lei JH, Liu LR, Wei Q, et al. Systematic review and meta-analysis of the survival outcomes of first-line treatment options in high-risk prostate cancer. Sci Rep 2015;5:7713.

5. Johnston TJ, Shaw GL, Lamb AD, et al. Mortality Among Men with Advanced Prostate Cancer Excluded from the Protect Trial. Eur Urol 2017;71(3):381-8.

6. Heidenreich A, Pfister D, Porres D. Cytoreductive radical prostatectomy in patients with prostate cancer and low volume skeletal metastases: Results of a feasibility and case-control study. J Urol 2015:193(3):832-8.

7. Ghadjar P, Briganti A, De Visschere PJL, et al. The oncologic role of local treatment in primary metastatic prostate cancer. World J Urol 2015:33(6):755-61.

8. Di Benedetto A, Soares R, Dovey Z, et al. Laparoscopic radical prostatectomy for high-risk prostate cancer. BJU Int 2015;115(5):780-6.

9. Everaerts W, Van Rij S, Reeves F, et al. Radical treatment of localised prostate cancer in the elderly. BJU Int 2015;116(6):847-52.

10. Gözen AS, Akin Y, Ates M, et al. Impact of laparoscopic radical prostatectomy on clinical T3 prostate cancer: Experience of a single centre with long-term follow-up. BJU Int 2015;116(1):102-8.

11. Bratt o, Folkvaljon Y, Eriksson MH, et al. Undertreatment of men in their seventies with high-risk nonmetastatic prostate cancer. Eur Urol 2015;68(1):53-8.

12. Wiegel T, Bartkowiak D, Bottke D, et al. Prostate-specific antigen persistence after radical prostatectomy as a predictive factor of clinical relapse-free survival and overall survival: 10-year data of the ARO 96-02 trial. Int J Radiat Oncol Biol Phys 2015:91(2):288-94.

13. Abdollah F, Klett DE, Sood A, et al, Predicting pathological outcomes in patients undergoing robot-assisted radical prostatectomy for high-risk prostate cancer: A preoperative nomogram. BJŲ Int 2015;116(5):703-12.

14. Jo JK, Kook HR, Byun S-S, et al. Stratification of Contemporary Patients Undergoing Radical Prostatectomy for High-risk Prostate cancer. Ann Surg Oncol 2015;22(6):2088-93.

15. Dell'Oglio P, Karnes RJ, Joniau S, et al. Very long-term survival patterns of young patients treated with radical prostatectomy for high-risk prostate cancer. Urol Oncol 2016;34(5):234.e13-9.

16. Briganti A, Karnes RJ, Gandaglia G, et al. Natural history of surgically treated high-risk prostate cancer. Urol Oncol 2015;33(4):163.e7-13.

17. Koie T, Mitsuzuka K, Yoneyama T, et al. Prostate-specific antigen density predicts extracapsular extension and increased risk of biochemical recurrence in patients with high-risk prostate cancer who underwent radical prostatectomy. Int J Clin Oncol 2015;20(1):176-81.

18. Lanchon C, Shariat SF, Roupret M. The role for surgery in high-risk prostate cancer. Wien Med Wochenschr 2015;165(19-20):395-400.

19. Djaladat H, Amini E, Xu W, Cai J, Daneshmand S, Lieskovsky G. Oncological Outcomes After Radical Prostatectomy for High-Risk Prostate cancer Based on New Gleason Grouping System: A Validation Study From University of Southern California With 3,755 Cases. Prostate 2017:77(7):743-8.

근거표

KQ15
Reference	1. Lei JH, Liu LR, Wei Q, et al. Systematic review and meta-analysis of the survival outcomes of first-line treatment options in high-risk prostate cancer. Sci Rep 2015;5:7713.  Study
Study type	Systematic review
Patients
Purpose of Study	To compare the long-term survival outcomes of RP, RT, BT, ADT, and watchful waiting (WW), alone or in combination, in patients with high-risk PCa.
Study Results	The overall priority for treatment strategy could be ranked as follows: RP/(RT plus ADT), RT, and ADT/WW. RP had significant better overall survival (OS) than RT or BT, and RP had significant lower cancer-specific mortality (CSM) than RT (0.51 [95% CI 0.30-0.73], P<0.001).
Level of Study	1
Reference	2. Johnston TJ, Shaw GL, Lamb AD, et al. Mortality Among Men with Advanced Prostate Cancer Excluded from the Protect Trial. Eur Urol 2017;71(3):381-8.
Study type	Large, multicenter, non-randomized controlled trial
Patients	492 men
Purpose of Study	To determine outcomes for men diagnosed with advanced PCa following prostate-specific antigen (PSA) testing who were excluded from the ProtecT randomised trial.
Study Results	All-cause mortality was 7% (4/54) among men who underwent RP (2 died of PCa; 4%) and 15% (37/245) among those who received RT (12 died of PCa; 5%). All-cause mortality was higher among men who underwent non-radical treatment (51/133; 38%) and men whose treatments were unknown (25/60; 42%; all p<0.0001) There was a much higher risk of death from PCa (HR 6.70, 95% CI 2.64-16.9; p<0.0001) and all causes (HR 4.55, 95% CI 2.42-8.52; p<0.0001) among men who received nonradical treatment compared to those who underwent radical treatment
Level of Study	2
Reference	3. Heidenreich A, Pfister D, Porres D. Cytoreductive radical prostatectomy in patients with prostate cancer and low volume skeletal metastases: Results of a feasibility and case-control study. J Urol 2015;193(3):832-8.
Study type	Case-control study
Patients	23 cytoreductive radical prostatectomy patients (Group 1) and 38 control patients (Group 2)
Purpose of Study	To explore the role of cytoreductive radical prostatectomy in prostate cancer with low volume skeletal metastases in terms of a in terms of a feasibility study.
Study Results	Median time to castration resistant prostate cancer was 40 months (range 9 to 65) and 29 months (range 16 to 59) in groups 1 and 2, respectively (p=0.04). Patients in group 1 experienced significantly better clinical progression-free survival (38.6 vs 26.5 months, p=0.032) and cancer specific survival rates (95.6% vs 84.2%, p=0.043), whereas overall survival was similar.
Level of Study	2
Reference	4. Ghadjar P, Briganti A, De Visschere PJL, et al. The oncologic role of local treatment in primary metastatic prostate cancer. World J Urol 2015;33(6):755-61.
Study type	Systematic Review
Patients
Purpose of Study	To determine the oncologic benefit or otherwise of local treatment of the prostate in patients with primary metastatic prostate cancer.
Study Results	Retrospective series and population-based data suggest that the use of local treatment of the prostate in patients with primary metastatic prostate cancer may improve cancerspecific survival and overall survival com- pared with treating these patients with androgen depriva- tion therapy alone. The clinical outcome in metastatic pros- tate cancer is largely determined by the extent of lymph node involvement and overall metastatic burden. Contemporary data are lacking to recommend one alternative of local therapy (radiotherapy or radical prostatectomy) over the other.  Level
Level of Study	1
Reference	5. Di Benedetto A, Soares R, Dovey Z, et al. Laparoscopic radical prostatectomy for high-risk prostate cancer. BJU Int 2015;115(5):780-6.
Study type	Cohort study
Patients	446 patients
Purpose of Study	To investigate the results of performing laparoscopic radical prostatectomy (LRP) in patients with high-risk prostate cancer (HRPC): PSA level of ≥20 ng/mL ± biopsy Gleason ≥8 ± clinical T stage ≥2c.
Study Results	The low morbidity, 55.4% specimen-confinement rate, 26.0% PSM rate, 79.2% biochemical disease-free survival, 91.8% continence rate and 64.4% potency rate, at 35.2 months in the present study serve as evidence firstly that surgery is an effective treatment for patients with HRPC, curing many and representing the first step of multi-modal treatment for others, and that LRP for HRPC appears to be as effective as open RP in this context.
Level of Study	2
Reference	6. Everaerts W, Van Rij S, Reeves F, et al. Radical treatment of localised prostate cancer in the elderly. BJU Int 2015;116(6):847-52.
Study Results	Systematic Review
Patients
Purpose of Study	To review addresses the evidence for radical treatment of clinically localised intermediate- and high-risk prostate cancer in older men
Study Results	Results from this study showed a lack of benefit for treatment in those with low-risk prostate cancer. However, in those with intermediate- to high-risk disease there was a strong trend to a decrease in all-cause mortality
Level of Study	1
Reference	7. Gözen AS, Akin Y, Ates M, et al. Impact of laparoscopic radical prostatectomy on clinical T3 prostate cancer: Experience of a single centre with long-term follow-up. BJU Int 2015;116(1):102-8.
Study type	Case-control study
Patients	417 patients (cT1), 842 patients (cT2), 492 patients (cT3)
Purpose of Study	To investigate the oncological safety and effectiveness of laparoscopic radical prostatectomy (LRP) for patients with clinical T3 (cT3) prostate cancer compared with patients with cT1 and cT2 prostate cancer. Group 3 showed 99.8%, 97.4 of cancer-specific survival at 5, 10 year follow-up respectively. Its overall survival at 5, 10 years were 99.1, 93.4% respectively.
Study Results	Group 1 had the best cancer-specific survival rate, whereas overall survival (OS) rates and complications were similar in all groups.
Level of Study	2
Reference	8. Bratt O, Folkvaljon Y, Eriksson MH, et al. Undertreatment of men in their seventies with high-risk nonmetastatic prostate cancer. Eur Urol 2015;68(1):53-8.
Study type	Cohort study
Patients	19,190 patient
Purpose of Study	To investigate how age and comorbidity affect treatment of men with HRnMPCa.
Study Results	Otherwise healthy men in their seventies with HRnMPCa were less likely to receive radical treatment than younger men with a similar life expectancy, although increasing use of radical treatment was observed during the study period. Our findings highlight the need for improved methods for clinical decision-making, including improved assessment of life expectancy.
Level of Study	2
Reference	9. Wiegel T, Bartkowiak D, Bottke D, et al. Prostate-specific antigen persistence after radical prostatectomy as a predictive factor of clinical relapse-free survival and overall survival: 10year data of the ARO 96-02 trial. Int J Radiat Oncol Biol Phys 2015;91(2):288-94.
Study type	Cohort study
Patients	388 patients with pT3-4pN0 prostate cancer with positive or negative surgical margins
Purpose of Study	To report the outcome with up to 12 years of follow-up of patients who retained a post-RP detectable PSA and received salvage radiation therapy
Study Results	Patients who detained post-RP detectable PSA had worse outcome results compared with those whose post-RP PSA was undetectable (a 10-year metastasis-free survival of 67% versus 83%and overall survival of 68% versus 84%, respectively)
Level of Study	2
Reference	10. Abdollah F, Klett DE, Sood A, et al. Predicting pathological outcomes in patients undergoing robot-assisted radical prostatectomy for high-risk prostate cancer: A preoperative nomogram. BJU Int 2015;116(5):703-12.
Study type	Cohort study
Patients	810 patients
Purpose of Study	To identify which high-risk patients with prostate cancer may harbor favourable pathological outcomes at radical prostatectomy
Study Results	Patients with specimen confined disease (SCD) had significantly higher 8-year biochemical recurrence (72.7% vs 31.7%, P<0.001) and cancer-specific free survival rates (100% vs 86.9%, P<0.001) than patients with non-SCD.
Level of Study	2
Reference	11. Jo JK, Kook HR, Byun S-S, et al. Stratification of Contemporary Patients Undergoing Radical Prostatectomy for High-risk Prostate Cancer. Ann Surg Oncol 2015;22(6):2088-93.
Study type	Cohort study
Patients	1,905 patients
Purpose of Study	To identify more precise risk stratification system for contemporary high-risk prostate cancer.
Study Results	primary Gleason 5 pattern on biopsy (p=0.008) and multiple (C2) high-risk criteria (p<0.001) were observed to be independent predictors of the risk of biochemical recurrence amongst high-risk group undergoing RP
Level of Study	2
Reference	12. Dell’Oglio P, Karnes RJ, Joniau S, et al. Very long-term survival patterns of young patients treated with radical prostatectomy for high-risk prostate cancer. Urol Oncol 2016;34(5):234.e13-9.
Study type	Multicenter longitudinal study
Patients	446 patients
Purpose of Study	To evaluate long-term survival patterns in young patients treated with radical prostatectomy (RP) for HRPCa.
Study Results	The 10-, 15- and 20-year CSM and OCM rates were 11.6% and 5.5% vs. 15.5% and 13.5% vs. 18.4% and 19.3%, respectively. The 5-year probability of CSM and OCM rates among patients who survived at 5, 10, and 15 years after RP, were 6.4% and 2.7% vs. 4.6% and 9.6% vs. 4.2% and 8.2%, respectively. Year of surgery, pathological stage and Gleason score, surgical margin status and lymph node invasion were the major determinants of CSM (all P≤0.03). Conversely, none of the covariates was significantly associated with OCM (all P≥0.09).
Level of Study	2
Reference	13. Briganti A, Karnes RJ, Gandaglia G, et al. Natural history of surgically treated high-risk prostate cancer. Urol Oncol 2015;33(4):163.e7-3.
Study type	Multicenter longitudinal study
Patients	2,065 patients
Purpose of Study	To evaluate the natural history of PCa in patients treated with radical prostatectomy (RP) alone.
Study Results	Overall, the 5-year BCR-free survival rate was 55.2%. Given the BCR-free survivorship at 1, 2, 3, 4, and 5 years, the BCR-free survival rates improved by +7.6%, +4.1%, +4.8%, +3.2%, and +3.7%, respectively. Overall, the 10-year CSM rate was 14.8%. When patients were stratified according to time to BCR, patients experiencing BCR within 36 months from surgery had higher 10-year CSM rates compared with those experiencing late BCR (19.1% vs. 4.4%; P<0.001). At multivariate analyses, time to BCR represented an independent predictor of CSM (P<0.001)
Level of Study	2
Reference	14. Koie T, Mitsuzuka K, Yoneyama T, et al. Prostate-specific antigen density predicts extracapsular extension and increased risk of biochemical recurrence in patients with highrisk prostate cancer who underwent radical prostatectomy. Int J Clin Oncol 2015;20(1):17681.  Study
Study type	Multicenter longitudinal study
Patients	380 high risk patients
Purpose of Study	To predict pathological and oncological outcomes in high-risk PCa patients who underwent RP
Study Results	PSAD was an independent predictor of adverse pathologic stage. The 5-year PSA-free survival rates were 82.9% for patients with PSAD≤0.468 and 50.7% for those with PSAD>0.468 (P<0.0001).
Level of Study	2
Reference	15. Lanchon C, S FS, Roupret M. The role for surgery in high-risk prostate cancer. Wien Med Wochenschr 2015;165(19-20):395-400.
Study type	Review
Patients
Purpose of Study	To analyze clinical outcomes after RP for high-risk PCa and to determine the role of surgery compared with other possible treatments in this population.
Study Results	Recent series have shown very promising results of radical prostatectomy (RP)—alone or part as a multimodality approach— in patients with high-risk PCa, with satisfactory survival curves even though biochemical recurrence rate was high. Adjuvant treatment (radiotherapy (RT) alone or combined with androgen deprivation) was necessary in 20 to 54% of patients, notably in cases with positive surgical margins. As for functional outcomes, urinary continence was preserved in about 92% of cases and overall potency in 60%. When comparing RP versus RT as primary treatment for high-risk PCa, a recent meta- analysis found surgery to be associated with an improved cancer-specific mortality compared with RT.
Level of Study	1
Reference	16. Djaladat H, Amini E, Xu W, et al. Oncological Outcomes After Radical Prostatectomy for High-Risk Prostate Cancer Based on New Gleason Grouping System: A Validation Study From University of Southern California With 3,755 Cases. Prostate 2017;77(7):743-8.
Study type	Retrospective cohort study
Patients	226 (GS 8) and 132 (GS 9-10) patients
Purpose of Study	To assess the prognostic value of new Gleason grade grouping system in high-risk prostate cancer patients, we compared oncological outcomes after radical prostatectomy for patients with Gleason score 8 versus 9-10
Study Results	Gleason 9-10 prostate cancer was associated with worse biochemical (HR 1.6; 95%CI [1.1-2.3]) and clinical recurrence free survival (HR 1.9; 95%CI [1.1-3.3]); however, overall survival did not differ significantly between the groups. Significant differences were in disease-specific outcomes between patients with Gleason score 8 versus 9-10.
Level of Study	2

 

KO 16. 고위험 전립선암 환자에서 근치적 전립선 절제술 후 림프절 전이가 확인된 경우 남성호르몬 박탈용법을 보조적으로 투여하는 것이 생화학적 재발이 확인된 이후 시작하는 것보다 생존율이 높은가?

권고사항	권고수준	근거수준
고위험 전립선암 환자에서 근치적 전립선 절제술과 골반림프절절제술 후 림 프절 전이가 확인되면 보조적 남성호르몬 박탈요법을 권고한다.	B	II

개요

고위험 전립선암 환자에서는 근치적 전립선 절제술을 시행한 후에도 생화학적 재발이나 임상적 전이로 인하여 추가적인 치료가 필요한 경우가 많으며^[1] 특히 근치적 전립선 절제술 및 골반림프절 절제술을 시행 받은 후 림프절 전이가 확인된 환자들은 예후가 좋지 않다^[2,3]. 따라서 근치적 전립선 절제술 후 림프절 전이가 확인된 경우에는 추가적으로 체외방사선요법을 시행하거나^[4] 남성호르몬 박탈요법을 시행할 수가 있는데 추가 치료의 적절한 시기와 방법에 대해서는 아직 논란이 존재한다.

Messing 등은 Eastern Cooperative Oncology Group (ECOG) randomized clinical trial에서 98명의 근치적 전립선 절제술 후 림프절 전이가 있는 환자들을 대상으로 남성호르몬 박탈요법을 즉시 시행한 군과 생화학적 재발 때까지 기다린 후 시행한 군을 비교한 후 즉각적인 남성호르몬 박탈 요법이 생존율을 향상시킨다는 연구 결과를 발표하였다. 47명의 남성호르몬 치료 군과 51명의 대조군을 비교하여 분석하였으며 즉각적인 남성호르몬 박탈요법을 시행한 군에서 전체 생존율이 유의하게 높았음을 확인하였다(Hazard ratio=1.84 [95% CI 1.01 to 3.35], p=0.04)^[5]. 하지만 등록된 환자 수가 적고 연구 디자인에 한계점이 발견되어 신뢰성은 떨어지는 것으로 알려져 있다. Boorjian 등은 2007년 507명의 근치적 전립선 절제술 후 림프절 전이가 있는 환자들을 대상으로 즉각적인 남성호르몬 박탈 요법 여부에 따라 생존율을 비교 분석하였다. 총 455명(89.7%)이 수술 후 즉각적인 남성호르몬 박탈요법을 시행 받았으며 이는 생화학적 재발의 위험과(P<0.001) 국소 재발의 위험을 유의하게 낮추었다 (P=0.004). 하지만 암의 전신으로의 진행과 질병 특이 생존율에는 영향을 주지 못하였다(p=0.4)^[6].

또한 2007년 업데이트된 American Society of Clinical Oncology (ASCO) 가이드라인에선 기존의 임상 연구와 논문들을 메타 분석하여 전이성 또는 진행성 전립선암 환자에서 즉각적인 남성호르몬 박탈 요법은 질병 특이 사망률에 대한 상대적 위험도를 17% 감소시키나 질병 비 특이 사망률에 대한 상대적 위험도는 15% 증가시켜 전체 생존율에는 영향을 주지 않는 것으로 보고하였다^[7-11]. 이후 Wong 등에 의한 연구에서도 731명의 림프절 전이가 있는 환자 중에 209명이 120일 이내의 호르몬 박탈 요법을 받았으나 전체 생존율은 증가시키지 못한 것으로 발표되었다(Hazard ratio=0.97 [95% CI 0.71 to 1.27]). 또한 질병 특이 생존율에도 유의한 차이가 없었다(Hazard ratio=0.97 [95% CI 0.56 to 1.68])^[12]. 국내에서도 Park 등이 근치적 전립선 절제술 후 림프절 전이가 있는 40명을 대상으로 후향적 분석을 시행하였다. 즉각적인 남성호르몬 박탈요법을 시행 받은 군과(n=18) 대조 군(n=22)을 비교하였으며 5년 무 진행 생존율, 질병 특이 생존율, 전체 생존율은 남성호르몬 치료 군에서 각각 72.2%, 83.3%, 72.2%, 그리고 대조 군에서는 각각 77.2%, 86.4%, 72.8%로 차이가 없음을 발표하였다^[13].

따라서 현재까지의 발표된 논문 및 가이드라인에서는 즉각적인 남성호르몬 박탈 요법이 전체 생존율 향상에 기여한다는 확실한 근거는 없으므로 의사의 판단이 가장 중요하며 즉각적인 남성호르몬 박탈 요법을 강하게 권고하지 않고 있다.

기존 가이드라인 요약 및 수용성, 적용성 평가

2015년 대한비뇨기종양학회가 발간한 전립선진료지침에 따르면 골반림프절절제술 후 림프절 전이가 확인된 경우 남성호르몬 박탈요법을 시작하는 것을 권고하고 있으나^[5] 경우에 따라 술 후 PSA감시를 통하여 재발이 확인된 이후 치료를 시작할 수도 있다고 기술되어 있다^[11,12]. 2016년 EAU(European Association of Urology) 가이드라인에서는 골반림프절절제술 후 림프절 전이가 확인된 경우 남성호르몬 박탈요법을 시작하는 것을 권고하고는 있으나 광범위림프절 절제술 후 림프절 전이가 2개 이하이면서 PSA <0.1 ng/mL, 전이 림프절의 피막 외 침범이 없을 경우에는 경과 관찰을 할 수 있다고 기술하고 있다^[5,14]. 2016년 NCCN (National Comprehensive Cancer Network) 가이드라인에서는 즉각적인 남성호르몬 박탈요법을 시작하거나(category 1) 경과 관찰 후 증상의 발현이나 PSA 상승이 있을 경우 시작할 수 있다고 기술하고 있다^[5,11,12]. 그러나 2014년 NICE (National Institute for Health and Care Excellence) 및 2010년 CCAACN (Cancer Council Australia/Australian Cancer Network) 가이드라인에서는 2006년 발표된 Cochrane database of systematic review에서 5년 전체 생존율에 차이가 없는 것을 인용하여(P=0.2) 골반림프절절제술 후 림프절 전이가 확인되더라도 즉각적인 남성호르몬 박탈요법을 시작하는 것은 권고하지 않고 있다^[5,15].

KQ 16. 고위험 전립선암 환자에서 근치적 전립선 절제술 후 림프절 전이가 확인된 경우 남성호르몬 박탈용법을 보조적 으로 투여하는 것이 생화학적 재발이 확인된 이후 시작하는 것보다 생존율이 높은가?
지침(제목)	권고	권고등급	근거수준	page
1. 2015 KUOS	골반림프절절제술 후 림프절 전이가 확인된 경우 남성호르몬 박탈요법을 시작한다. 하지만, 경우에 따라 술 후 PSA 감시를 통하여 재발이 확인된 이후 치료를 시작할 수도 있다.	A	1b	28
2. EAU 2016	Upon detection of nodal involvement during RP: • Offer adjuvant ADT for node-positive (pN+); 1b A • Discuss adjuvant ADT with additional radiotherapy ; 2b A • Offer observation (expectant management) to a patient after eLND and < 2 nodes show microscopic involvement with a PSA < 0.1 ng/mL and absence of extranodal extension. 2b B	A	1b (LN  pathology  결과에 따 라 설명하 고 있음)	36
5. NCCN 2016	Lymph node metastasis: ADT (category 1) ± EBRT (category 2B) or Observation	A	Ib	PROS-5
6. NICE 2014	Do not offer adjuvant hormonal therapy in addition to radical prostatectomy, even to men with margin-positive disease, other than in the context of a clinical trial.	A	Ib	263
9. CCAACN 2010	For locally advanced prostate cancer (pT3 or higher), anti-androgens as an adjuvant monotherapy to radical prostatectomy are not recommended.	B	II	34

지침(제목)		1. 2015 KUOS	2. EAU 2016	5. NCCN 2016	6. NICE 2014	9. CCAACN 2010
수용성	인구 집단(유병률, 발생률 등)이 유사하다.	예	아니오	아니오	아니오	아니오
	가치와 선호도가 유사하다.	예	예	예	예	예
	권고로 인한 이득은 유사하다	예	예	예	예	예
	해당 권고는 수용 할 만하다.	예	예	예	아니오	아니오
적용성	해당 중재/장비는 이용 가능하다.	예	예	예	예	예
	필수적인 전문기술이 이용 가능하다.	예	예	예	예	예
	법률적/제도적 장벽이 없다.	예	예	예	예	예
	해당 권고는 적용 할 만하다.	예	예	예	아니오	아니오

가이드라인이 서로 다른 권고를 보여주고 있고 내용상 즉각적인 치료를 권고하지 않는 부분이 있다. 하지만 재발이나 림프절 전이여부에 따라 치료를 권고하고 있다. 이러한 관점에서 적용성과 수용성 여부를 판단하였다.

업데이트 근거 요약

근치적 전립선 절제술 후 림프절 전이가 있는 환자에서 즉각적인 남성호르몬 박탈요법을 시행하는 것이 생존율 향상에 이점이 있는지에 대해서는 대규모 무작위 대조군 시험이 부족한 관계로 아직 논란이 존재한다. 하지만 2017년도 발표된 대규모 다 기관 연구에서 Touijer 등은 1338명의 근치적 전립선 절제술 후 림프절 전이가 있는 환자들을 경과 관찰 군(28%), 남성호르몬 박탈요법 시행 군(49%), 남성호르몬 박탈요법과 체외방사선요법을 같이 시행한 군(23%)으로 나누어 생존율을 비교한 결과 즉각적인 남성호르몬 박탈요법을 시행한 군이 생화학적 재발 때까지 경과 관찰한 군에 비해 질병 특이 생존율은 유의하게 향상시켰으나(Hazard ratio=0.64, 95% CI: 0.43 to 0.95, p=0.027) 전체 생존율에는 영향을 미치지 못했다고 보고하였다(Hazard ratio=0.9, 95% CI: 0.65 to 1.25, p=0.5)^[16].

이러한 결과는 남성호르몬 박탈요법으로 인한 종양학적 생존율 증가가 질병 비특이적 사망률 증가로 인해 상쇄되고 있음을 의미한다. 앞선 연구들에서도 수술 후 남성호르몬 박탈요법은 전체 생존율은 증가시키지 못했으나 질병 특이 사망률에 대한 위험은 감소시키며 생화학적 재발과 국소 재발의 위험을 낮춘다는 결과는 보고되어 왔다^[6,11]. 하지만 수술 후 남성호르몬 박탈요법의 명확한 시작 시기에 대해서는 2018년 업데이트된 NCCN (National Comprehensive Cancer Network) 가이드라인에서도 여전히 경과 관찰 후 증상의 발현이나 PSA 상승이 있을 경우 시작 할 수 있다고 기술하고 있어 반드시 즉각적으로 치료를 시작하도록 권고하기는 어렵다.

참고문헌

1. Yossepowitch O, Eggener SE, Bianco FJ, Jr., Carver BS, Serio A, Scardino PT, et al, Radical prostatectomy for clinically localized, high risk prostate cancer: critical analysis of risk assessment methods. The Journal of Urology 2007;178(2):493-9; discussion 9.

2. 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. The Journal of Urology 2004;172(6 Pt 1):2252-5.

3. Zwergel U, Lehmann J, Wullich B, Schreier U, Remberger K, Zwergel T, et al. Lymph node positive prostate cancer: long-term survival data after radical prostatectomy. The Journal of Urology 2004:171(3):1128-31.

4. Abdollah F, Karnes RJ, Suardi N, Cozzarini C, Gandaglia G, Fossati N, et al. Impact of adjuvant radiotherapy on survival of patients with node-positive prostate cancer. Journal of clinical oncology: official journal of the American Society of Clinical Oncology 2014;32(35):3939-47.

5. Messing EM, Manola J, Yao J, Kiernan M, Crawford D, Wilding G, et al. Immediate versus deferred androgen deprivation treatment in patients with node-positive prostate cancer after radical prostatectomy and pelvic lymphadenectomy. The Lancet Oncology 2006;7(6):472-9.

6. Boorjian SA, Thompson RH, Siddiqui S, Bagniewski S, Bergstralh EJ, Karnes RJ, et al. Long-term outcome after radical prostatectomy for patients with lymph node positive prostate cancer in the prostate specific antigen era. The Journal of Urology 2007;178(3 Pt 1):864-70; discussion 70-1.

7. Schroder FH, Kurth KH, Fossa SD, Hoekstra W, Karthaus PP, Debois M, et al. Early versus delayed endocrine treatment of PN1-3 MO prostate cancer without local treatment of the primary tumor: results of European Organisation for the Research and Treatment of Cancer 30846--a phase III study. The Journal of Urology 2004;172(3):923-7.

8. Kirk D. Timing and choice of androgen ablation. Prostate cancer and Prostatic Diseases 2004:7(3):217-22.

9. Nair B, Wilt T, MacDonald R, Rutks I. Early versus deferred androgen suppression in the treatment of advanced prostatic cancer. The Cochrane Database of Systematic Reviews 2002(1):Cd003506.

10. Messing EM, Manola J, Sarosdy M, Wilding G, Crawford ED, Trump D. Immediate hormonal therapy compared with observation after radical prostatectomy and pelvic lymphadenectomy in men with node positive prostate cancer. The New England Journal of Medicine 1999:341(24):1781-8.

11. Loblaw DA, Virgo KS, Nam R, Somerfield MR, Ben-Josef E, Mendelson DS, et al. Initial hormonal management of androgen-sensitive metastatic, recurrent, or progressive prostate cancer: 2006 update of an American Society of Clinical Oncology practice guideline. Journal of Clinical Oncology 2007:25(12):1596 605.

12. Wong YN, Freedland S, Egleston B, Hudes G, Schwartz JS, Armstrong K. Role of androgen deprivation therapy for node-positive prostate cancer. Journal of Clinical Oncology 2009;27(1):100-5.

13. Park S, Kim SC, Kim W, Song C, Ahn H. Impact of adjuvant androgen-deprivation therapy on disease prog ression in patients with node-positive prostate cancer. Korean Journal of Urology 2011;52(11):741-5.

14. Ghavamian R, Bergstralh EJ, Blute ML, Slezak J, Zincke H. Radical retropubic prostatectomy plus orchiectomy versus orchiectomy alone for pTxN+ prostate cancer: a matched comparison. The Journal of Urology 1999:161(4):1223-7; discussion 7-8.

15. Kumar S, Shelley M, Harrison C, Coles B, Wilt TJ, Mason MD. Neo-adjuvant and adjuvant hormone therapy for localised and locally advanced prostate cancer. The Cochrane Database of Systematic Reviews 2006(4):Cd006019.

16. Touijer KA, Karnes RJ, Passoni N, Sjoberg DD, Assel M, Fossati N, et al. Survival Outcomes of Men with Lymph Node-positive Prostate Cancer After Radical Prostatectomy: A Comparative Analysis of Different Postoperative Management Strategies. European Urology 2017.

근거표

KQ16
Reference	1. Messing EM, Manola J, Yao J, Kiernan M, Crawford D, Wilding G, et al. Immediate versus deferred androgen deprivation treatment in patients with node-positive prostate cancer after radical prostatectomy and pelvic lymphadenectomy. The Lancet Oncology 2006;7(6):472-9.
Study type	Randomized controlled trial
Patients	Immediate ADT (n=47) and observed (n=51)
Purpose of Study	To determine whether immediate ADT extends survival in men with node-positive prostate cancer who have undergone radical prostatectomy and pelvic lymphadenectomy compared with those who received ADT only once disease progressed
Study Results	At median follow-up of 11.9 years (range 9.7-14.5 for surviving patients), men assigned immediate ADT had a significant improvement in overall survival (hazard ratio 1.84 [95% CI 1.01-3.35], p=0.04), prostate-cancer-specific survival (4.09 [1.76-9.49], p=0.0004), and progression-free survival (3.42 [1.96-5.98], p<0.0001). Of 49 histopathology slides received (19 immediate ADT, 30 observation), 16 were downgraded from the original Gleason score (between groups ≤6, 7, and ≥8) and five were upgraded. We recorded similar proportions of score changes in each group (p=0.68), and no difference in score distribution by treatment (p=0.38). After adjustment for score, associations were still significant between treatment and survival (overall, p=0.02; disease-specific, p=0.002; progression-free survival, p<0.0001).
Level of Study	1
Reference	2. Boorjian SA, Thompson RH, Siddiqui S, Bagniewski S, Bergstralh EJ, Karnes RJ, et al. Long-term outcome after radical prostatectomy for patients with lymph node positive prostate cancer in the prostate specific antigen era. The Journal of Urology 2007;178(3 Pt 1):864-70; discussion 70-1.
Study type	Case-control study
Patients	Of the 507 patients 455 (89.7%) were treated with adjuvant hormonal therapy
Purpose of Study	To examine the impact of lymph node metastases on the outcome of patients following radical prostatectomy and investigated prognostic factors that affect survival
Study Results	Ten-year cancer specific survival for patients with positive lymph nodes was 85.8% with 56% of the men free from biochemical recurrence at last followup. On multivariate analysis pathological Gleason score 8-10 (p=0.004), positive surgical margins (p=0.016), nondiploid tumor ploidy (p=0.023) and 2 or greater positive nodes (p=0.001) were adverse predictors of cancer specific survival. Tumor stage, year of surgery and total number of nodes removed did not significantly affect outcome. Adjuvant hormonal therapy decreased the risk of biochemical recurrence (p<0.001) and local recurrence (p=0.004) but it was not associated with systemic progression (p=0.4) or cancer specific survival (p=0.4)
Level of Study	3
Reference	3. Loblaw DA, Virgo KS, Nam R, Somerfield MR, Ben-Josef E, Mendelson DS, et al. Initial hormonal management of androgen-sensitive metastatic, recurrent, or progressive prostate cancer: 2006 update of an American Society of Clinical Oncology practice guideline. Journal of Clinical Oncology 2007;25(12):1596-605.
Study type	Systematic review, Meta-analysis
Patients	Seven randomized controlled trials (four new), one systematic review, one meta-analysis (new), one Markov model, and one delta-method 95% CI procedure for active controlled trials (new) informed the guideline update.
Purpose of Study	To update the 2004 American Society of Clinical Oncology (ASCO) guideline on initial hormonal management of androgen-sensitive, metastatic, recurrent, or progressive prostate cancer (PCa).
Study Results	In metastatic or progressive PCa, immediate versus symptom-onset institution of ADT results in a moderate decrease (17%) in relative risk (RR) for PCa-specific mortality, a moderate increase (15%) in RR for non-PCa-specific mortality, and no overall survival advantage. Therefore, the Panel cannot make a strong recommendation for early ADT initiation.
Level of Study	1
Reference	4. Messing EM, Manola J, Sarosdy M, Wilding G, Crawford ED, Trump D. Immediate hormonal therapy compared with observation after radical prostatectomy and pelvic lymphadenectomy in men with node-positive prostate cancer. The New England Journal of Medicine 1999;341(24):1781-8.
Study type	Randomized controlled trial
Patients	Ninety-eight men who underwent radical prostatectomy and pelvic lymphadenectomy and who were found to have nodal metastases were randomly assigned to receive immediate antiandrogen therapy
Purpose of Study	Because the optimal timing of the institution of antiandrogen therapy for prostate cancer is controversial, we compared immediate and delayed treatment in patients who had minimal residual disease after radical prostatectomy.
Study Results	After a median of 7.1 years of follow-up, 7 of 47 men who received immediate antiandrogen treatment had died, as compared with 18 of 51 men in the observation group (P=0.02). The cause of death was prostate cancer in 3 men in the immediatetreatment group and in 16 men in the observation group (P<0.01). At the time of the last follow-up, 36 men in the immediate-treatment group (77 percent) and 9 men in the observation group (18 percent) were alive and had no evidence of recurrent disease, including undetectable serum prostate-specific antigen levels (P<0.001). In the observation group, the disease recurred in 42 men; 13 of the 36 who were treated had a complete response to local treatment or hormonal therapy (or both), 16 died of prostate cancer, and 1 died of another disease. The remaining men in this group were alive with progressive disease at the time of the last follow-up or had had a recent relapse. Except for the treatment group (immediate therapy or observation), no clinical or histologic characteristic significantly influenced the outcome.
Level of Study	1
Reference	5. Wong YN, Freedland S, Egleston B, Hudes G, Schwartz JS, Armstrong K. Role of androgen deprivation therapy for node-positive prostate cancer. Journal of Clinical Oncology 2009;27(1):100-5.
Study type	Case-control study
Patients	A total of 731 men were identified, 209 of whom received ADT within 120 days of RP
Purpose of Study	To determine the impact of adjuvant androgen deprivation therapy (ADT) for patients who have node-positive prostate cancer in the prostate-specific antigen (PSA) era
Study Results	There was no statistically significant difference in OS between the adjuvant ADT and nonADT group (HR, 0.97; 95% CI, 0.71 to 1.27). There was no statistically significant survival difference with 90, 150, 180, and 365 days as the adjuvant ADT definition.
Level of Study	3
Reference	6. Park S, Kim SC, Kim W, Song C, Ahn H. Impact of adjuvant androgen-deprivation therapy on disease progression in patients with node-positive prostate cancer. Korean Journal of Urology 2011;52(11):741-5.
Study Results	Case-control study
Patients	Of 937 patients who underwent RP, we identified 40 (4.2%) who had lymph node metastasis. A total of 18 received adjuvant ADT (ADT group) and 22 were observed (observation group).
Purpose of Study	The survival benefits of adjuvant androgen-deprivation therapy (ADT) in prostate cancer and lymph node metastasis remain unclear. We assessed the role of ADT in disease progression after radical prostatectomy (RP).
Study Results	The 5-year PFS, CSS, and OS of the entire cohort were 75.0%, 85.0%, and 72.5%, respectively. In the ADT group, 6 patients (33.3%) showed clinical progression at a median 42.7 months. The 5-year PFS, CSS, and OS rates of this group were 72.2%, 83.3%, and 72.2%, respectively. In the observation group, 14 patients (63.6%) received salvage therapy owing to BCR. Nine patients (40.9%) with BCR in the observation group showed clinical progression at a median 43.4 months after RP. The 5-year PFS, CSS, and OS rates of this group were 77.2%, 86.4%, and 72.8%, respectively. In the observation group, the BCR rate was lower in patients with pT3a or less disease than in those with pT3b disease.
Level of Study	3
Reference	7. Kumar S, Shelley M, Harrison C, Coles B, Wilt TJ, Mason MD. Neo-adjuvant and adjuvant hormone therapy for localised and locally advanced prostate cancer. The Cochrane Database of Systematic Reviews 2006(4):Cd006019.
Study type	Systematic review
Patients	MEDLINE (1966-2006), EMBASE, The Cochrane Library, Science Citation Index, LILACS, and SIGLE
Purpose of Study	The objective of this review was to undertake a systematic review and, if possible, a metaanalysis of neo-adjuvant and adjuvant hormone therapy in localised or locally advanced prostate cancer.
Study Results	Men with prostate cancer have different clinical outcomes based on their risk (T1-T2, T3-T4, PSA levels and Gleason score). However, the majority of studies included in this review did not report results by risk groups; therefore, it was not possible to perform sub-group analysis. Neo-adjuvant hormonal therapy prior to prostatectomy did not improve overall survival (OR 1.11, 95% CI 0.67 to 1.85, P=0.69). However, there was a significant reduction in the positive surgical margin rate (OR 0.34, 95% CI 0.27 to 0.42, P<0.00001) and a significant improvement in other pathological variables such as lymph node involvement, pathological staging and organ confined rates. There was a borderline significant reduction of disease recurrence rates (OR 0.74, 95% CI 0.55 to 1.0, P=0.05), in favour of treatment. The use of longer duration of neo-adjuvant hormones, that is either 6 or 8 months prior to prostatectomy, was associated with a significant reduction in positive surgical margins (OR 0.56, 95% CI 0.39 to 0.80, P=0.002). In one study, neo-adjuvant hormones prior to radiotherapy significantly improved overall survival for Gleason 2 to 6 patients; although, in two studies, there was no improvement in disease-specific survival (OR 0.99, 95% CI 0.75 to 1.32, P=0.97). However, there was a significant improvement in both clinical disease-free survival (OR 1.86, 95% CI 1.93 to 2.40, P<0.00001) and biochemical disease-free survival (OR 1.93, 95% CI 1.45 to 2.56, P<0.00001). Adjuvant androgen deprivation following prostatectomy did not significantly improve overall survival at 5 years (OR 1.50, 95% CI 0.79 to 2.85, P=0.2); although one study reported a significant disease-specific survival advantage with adjuvant therapy (P=0.001). In addition, there was a significant improvement in disease-free survival at both 5 years (OR 3.73, 95%CI 2.30 to 6.03, P<0.00001) and 10 years (OR 2.06, 95% CI 1.34 to 3.15, P=0.0009). Adjuvant therapy following radiotherapy resulted in a significant overall survival gain apparent at 5 (OR 1.46, 95% CI 1.17 to 1.83, P=0.0009) and 10 years (OR 1.44, 95% CI 1.13 to 1.84, P=0.003); although there was significant heterogeneity (P=0.09 and P=0.07, respectively). There was also a significant improvement in disease-specific survival (OR 2.10, 95% CI 1.53 to 2.88, P=0.00001) and disease-free survival (OR 2.53, 95% CI 2.05 to 3.12, P<0.00001) at 5 years.
Level of Study	1
Reference	8. Touijer KA, Karnes RJ, Passoni N, Sjoberg DD, Assel M, Fossati N, et al. Survival Outcomes of Men with Lymph Node-positive Prostate Cancer After Radical Prostatectomy: A Comparative Analysis of Different Postoperative Management Strategies. European Urology 2017.
Study Results	Case-control study
Patients	1,338 patients with LNM after RP from three tertiary care centers.
Purpose of Study	To evaluate the association between three different management strategies and survival in prostate cancer with LNM after RP.
Study Results	ADT+EBRT was associated with better OS than ADT alone (hazard ratio [HR]: 0.46, 95% confidence interval [CI]: 0.32-0.66, p<0.0001) or observation (HR: 0.41, 95% CI: 0.270.64, p<0.0001). Higher-risk patients benefited more from ADT+EBRT than lower-risk patients. Ten-year mortality risk difference between ADT+EBRT, observation, or ADT alone ranged from 5% in low-risk patients to 40% in high-risk patients. Adjuvant ADT+EBRT was also associated with better CSS than observation or ADT alone (p<0.0001), ADT had better CSS compared to observation (HR: 0.64, 95% CI: 0.43-0.95, p=0.027). However, ADT was associated with an increased risk of other-cause mortality (HR: 3.05, 95% CI: 1.45-6.40, p=0.003) compared with observation, resulting in similar OS between ADT and observation (HR: 0.90, 95% CI: 0.65-1.25, p=0.5).
Level of Study	3