KQ 7. 중간위험 전립선암환자에서 근치적 전립선절제술 후 병리학적 불량 예후인자를 보일 경우 추가적인 방사선치료를 하는 경우가 보조요법을 하지 않는 경우보다 생존율이 우수한가?

권고사항	권고수준	근거수준
중간위험 전립선암환자에서 근치적 전립선절제술 후 병리학적 불량 예후인자 를 보일 경우 보조 또는 구제 방사선치료를 할 수 있다.	A	I

개요

보조요법으로서 방사선치료에 대하여는 전향적 무작위 연구가 몇몇 기관에서 발표된 바 있으며, SWOG 8794 연구에서 근치적 전립선절제술 후 pT3 환자 425명의 환자를 대상으로 보조요법(EBRT, external beam radiotherapy)을 시행한 군과 그렇지 않은 군을 나누어 12.6년 추적관찰 하였을 때 보조요법을 시행한 군이 그렇지 않은 군에 비하여 재발율을 낮추어주는 것을 확인할 수 있었다^[1].

EORTC 연구에서는 1,005명의 병리학적 불량예후인자를 보이는 환자를 대상으로 보조요법(EBRT)을 시행한 군과 그렇지 않은 군을 나누어 비교하였을 때 5년 생화학적 무재발 생존율이 각각 78%, 49%로 보조요법을 시행한 군에서 좋은 결과를 보여 주었다^[2]. 또 다른 그룹에서 시행한 연구에서도 268명의 병리학적 불량예후 인자를 보이며 PSA가 측정되지 않았던 환자에서 술 후 보조방사선치료를 시행한 군에서 5년 생화학적 무재발 생존율이 72%, 54%로 보조요법을 시행한 군에서 좋은 결과를 확인할 수 있었다^[3].

기존 가이드라인 요약 및 수용성, 적용성 평가

NICE 2016 guideline에서는 “수술 직후(immediate postoperative) 방사선 요법”은 positive surgical margin에서도 권장하고 있지 않다. 하지만 EAU guideline, NCCN guideline 등 주요 진료지침에서는 전립선절제술 시행 후 병리학적으로 불량한 예후를 보일 때 특히 pT3, positive surgical margin, Gleason 점수 8점 이상, 정낭침범이 있는 경우 보조 방사선 치료를 권고하고 있다. 이러한 진료지침은 비교적 최근의 중요한 3개의 무작위 임상시험에서 나타난 보조 방사선 치료의 무생화학적 재발 측면에서의 우수성에 그 기반을 두고 있다고 할 수 있다^[4-6].

KQ 7. 중간위험 전립선암환자에서 근치적 전립선절제술 후 병리학적 불량 예후인자를 보일 경우 추가적인 방사선치료를 하는 경우가 보조요법을 하지 않는 경우보다 생존율이 우수한가?
지침(제목)	권고	권고등급	근거수준	Page
1. 2015 KUOS	유해한 병리학적 요소들을 갖거나 측정 가능한 PSA를 보이고 전이의 증거는 없는 대부분의 환자들에 있어 보조/구제 방사선치료는 권장된다.	없음	없음	24
2. EAU 2016	In patients with pT3,N0M0 Prostate cancer and an undetectable PSA following RP, discuss adjuvant EBRT because it improves at least biochemical-free survival.	A	1a	48
5. NCCN 2016	Indications for adjuvant RT include pT3 disease, positive margin(s), Gleason score 8-10, or seminal vesicle involvement. Adjuvant RT is usually given within 1 year after RP and once any operative side effects have improved/stabilized. Paitents with positive surgical margins may benefit the most.	없음	없음	PROS-D 2 of 2
6. NICE 2014	Do not offer immediate postoperative radiotherapy after radical prostatectomy, even to men with marginpositive disease, other than in the context of a clinical trial. There are two randomised trials which have not shown any improvement in survival from immediate post operative radiotherapy.	없음	없음	280
9. CCAACN 2010	It is recommended that patients with extracapsular extension, seminal vesicle involvement or positive surgical margins receive post-operative EBRT within four months of surgery. The role of active surveillance and early salvage radiotherapy has not been defined.	B	II	37

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	아니오	예
	권고로 인한 이득은 유사하다	예	예	예	불확실	예
	해당 권고는 수용할 만하다.	예	예	예	아니오	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 적용할 만하다.	예	예	예	아니오	예

NICE 2014에서 수용성은 국내 진료 현실과 다른 가이드라인과 차이나는 부분이 있었다. 적용성 부분은 크게 무리가 없었으나 치료 시기의 문제에 대해서 추가 논의가 필요한 부분이 있었다.

업데이트 근거 요약

최근에는 보조 방사선 요법과 조기 구제 방사선 치료가 우수한 측면이 없다는 연구 결과도 발표되고 있으나^[7] 후향적 연구로 앞에서 언급된 3가지의 무작위 임상시험에 비하여 근거의 신뢰성이 떨어진다. 특히 가장 최근 연구에서도 pT3 또는 절제면 양성인 환자에서 보조 방사선치료를 시행한 군이 조기 구제 방사선치료(early-salvage radiotherapy)를 시행한 군 보다 무생화학적 재발률이 우수한 것으로 나타났다^[8,9]. 따라서 전립선 절제술 후 병리학적 불량 예후 인자를 보이는 경우 특히 pT3 또는 절제면 양성 보이는 경우에는 보조 방사선 치료를 고려할 수 있다.

참고문헌

1. Thompson IM, Tangen CM, Paradelo J, et al. Adjuvant radiotherapy for pathological T3N0M0 prostate cancer significantly reduces risk of metastases and improves survival: long-term followup of a randomized clinical trial. J Urol 2009;181:956-62.

2. Van der Kwast TH, Bolla M, Van Poppel H, et al. Identification of patients with prostate cancer who benefit from immediate postoperative radiotherapy: EORTC 22911. J Clin Oncol 2007;25:4178-86.

3. Wiegel T, Bottke D, Steiner U, et al. Phase III postoperative adjuvant radiotherapy after radical prostatectomy compared with radical prostatectomy alone in pT3 prostate cancer with postoperative undetectable prostate-specific antigen: ARO 96-02/AUO AP 09/95. J Clin Oncol 2009;27:2924-30.

4. Bolla M, 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.

5. Wiegel T, 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.

6. 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.

7. Fossati N, 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(6):886-93.

8. Buscariollo DL, et al. Long-term results of adjuvant versus early salvage postprostatectomy radiation: A large single-institutional experience. Pract Radiat Oncol 2017;7(2):e125-33.

9. Hwang WL, et al. Comparison Between Adjuvant and Early-Salvage Post prostatectomy Radiotherapy for Prostate Cancer With Adverse Pathological Features. JAMA Oncol 2018:e175230. doi: 10.1001/jamaoncol.2017.5230. [Epub ahead of print]

근거표

KQ7
Reference	1. Van der Kwast TH, Bolla M, Van Poppel H, et al. Identification of patients with prostate cancer who benefit from immediate postoperative radiotherapy: EORTC 22911. J Clin Oncol 2007;25:4178-86.
Study type	Prospective Randomized trial
Patients	1,005
Purpose of Study	To evaluate the effect of radiotherapy after prostatectomy in patients with adverse risk factors
Study Results	Margin status assessed by review pathology was the strongest predictor of prolonged biochemical disease-free survival with immediate postoperative radiotherapy (heterogeneity, P<.01): by year 5, immediate postoperative irradiation could prevent 291 events/1,000 patients with positive margins versus 88 events/1,000 patients with negative margins. The hazard ratio for immediate irradiation was 0.38 (95% CI, 0.26 to 0.54) and 0.88 (95% CI, 0.53 to 1.46) in the groups with positive and negative margins, respectively. We could not identify a significant impact of the positive margin localization.
Level of Study	1
Reference	2. Bolla M, 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.
Study type	Prospective Randomized trial
Patients	1,005
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, to confirm whether previously reported progression-free survival was sustained
Study Results	1005 patients were randomly assigned to a wait-and-see policy (n=503) or postoperative irradiation (n=502) and were followed up for a median of 10.6 years (range 2 months to 16.6 years). Postoperative irradiation significantly improved biochemical progressionfree survival compared with the wait-and-see policy (198 [39.4%] of 502 patients in postoperative irradiation group vs 311 [61.8%] of 503 patients in wait-and-see group had biochemical or clinical progression or died; HR 0.49 [95% CI 0.41-0.59]; p<0.0001). Late adverse effects (any type of any grade) were more frequent in the postoperative irradiation group than in the wait-and-see group (10 year cumulative incidence 70.8% [66.6-75.0] vs 59.7% [55.3-64.1]; p=0.001).
Level of Study	1
Reference	3. Wiegel T, 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.
Study type	Prospective Randomized trial
Patients	388
Purpose of Study	To determine the efficiency of ART after a 10-yr follow-up in the ARO 96-02 study
Study Results	The median follow-up was 111 mo for ART and 113 mo for WS. At 10 yr, PFS was 56% for ART and 35% for WS (p<0.0001). In pT3b and R1 patients, the rates for WS even dropped to 28% and 27%, respectively. Of all 307 ITT2 patients, 15 died from PCa, and 28 died for other or unknown reasons. Neither metastasis-free survival nor overall survival was significantly improved by ART. However, the study was underpowered for these end points. The worst late sequelae in the ART cohort were one grade 3 and three grade 2 cases of bladder toxicity and two grade 2 cases of rectum toxicity. No grade 4 events occurred.
Level of Study	1
Reference	4. Hwang WL, et al. Comparison Between Adjuvant and Early-Salvage Postprostatectomy Radiotherapy for Prostate Cancer With Adverse Pathological Features. JAMA Oncol 2018;25:e175230.
Study type	Propensity score-matched cohort study
Patients	1,566
Purpose of Study	To compare the clinical outcomes of postoperative ART and ESRT administered to patients with prostatecancer with adverse pathological features.
Study Results	Of 1566 patients, 1195 with prostate-specific antigen levels lower than 0.1 ng/mL received ESRT and 371 patients with prostate-specific antigen levels of 0.1 to 0.5 ng/mL received ART. The median age (interquartile range) was 60 (55-65) years. After propensity score matching, the median (interquartile range) follow-up after surgery was similar between the ESRT and ART groups (73.3 [44.9-106.6] months vs 65.8 [40-107] months; P=.22). Adjuvant RT, compared with ESRT, was associated with higher freedom from biochemical failure (12-year actuarial rates: 69% [95% CI, 60%-76%] vs 43% [95% CI, 35%-51%]; effect size, 26%), freedom from distant metastases (95% [95% CI, 90%-97%] vs 85% [95% CI, 76%-90%]; effect size, 10%), and overall survival (91% [95% CI, 84%-95%] vs 79% [95% CI, 69%-86%]; effect size, 12%). Adjuvant RT, lower Gleason score and T stage, nodal irradiation, and postoperative androgen deprivation therapy were favorable prognostic features on multivariate analysis for biochemical failure. Sensitivity analysis demonstrated that the decreased risk of biochemical failure associated with ART remained significant unless more than 56% of patients in the ART group were cured by surgery alone. This threshold is greater than the estimated 12-year freedom from biochemical failure rate of 33% to 52% after radical prostatectomy alone, as determined by a contemporary dynamic nomogram.
Level of Study	2
Reference	5. Fossati N, et al. Long-term Impact of Adjuvant Versus Early Salvage Radiation Therapy in pT3N0Prostate Cancer Patients Treated with Radical Prostatectomy: Results from a Multiinstitutional Series. Eur Urol 2017;71(6):886-93.
Study type	Multicenter, retrospective 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	3
Reference	6. Buscariollo DL, et al. Long-term results of adjuvant versus early salvage postprostatectomy radiation: A large single-institutional experience. Pract Radiat Oncol 2017;7(2):e125-e133.
Study type	Retrospective study
Patients	718
Purpose of Study	To evaluate freedom from biochemical failure (FFBF), freedom from androgen deprivation therapy (FFADT), freedom from distant metastases (FFDM), and overall survival (OS) after adjuvant radiationtherapy (ART) versus early salvage radiation therapy (ESRT) in men with prostate cancer and adverse pathologic features (pT3 and/or positive surgical margins).
Study Results	Median follow-up was 7.4 and 8.0 years for patients treated with ART and ESRT, respectively. Ten-year FFBF (69% vs 56%, P=.003) and 10-year FFADT (88% vs 81%, P=.046) rates were higher after ART; however, FFDM and OS did not significantly differ. After PS-matching, ART was associated with improved FFBF (P<.0001), FFADT (P=.0001), and FFDM (P=.02). Findings were confirmed in multivariable analyses in unmatched and PS-matched cohorts. Sensitivity analyses showed that FFBF benefit associated with ART lost statistical significance only after 38% of ART patients were assumed to have been cured by surgery and excluded from the model. This corresponds to the upper bound of patients with adverse pathologic features who did not recur after observation in prior randomized trials.
Level of Study	3