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

{| class="wikitable mw-collapsible"
!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<sup>[1]</sup>. 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<sup>[2]</sup>.  

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<sup>[3,4]</sup> SPCG-7/SFUO-3 연구에서도 외부 방사선 치료와 남성 호르몬 박탈요법 병행군이 남성호르몬 박탈 요법 단독군에 비하여 좋은 예후를 보인다고 보고한 바 있다<sup>[5]</sup>. 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<sup>[6-9]</sup>. 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<sup>[10]</sup>. 

== 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<sup>[3-5,7]</sup>. EAU 진료지침에서도 고위험 전립선암 환자에서 76-78 Gy의 외부 방사선 치료와 장기간(2-3년) 남성 호르몬 박탈요법이 생존율 향상에 도움이 된다고 권고하고 있다<sup>[11]</sup>.

상기 연구결과들을 토대로<sup>[11-13]</sup> “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.

{| class="wikitable mw-collapsible"
! colspan="5" |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)
|}
{| class="wikitable mw-collapsible"
! colspan="2" |지침(제목)
!1. 2015 KUOS
!2. EAU 2016 
!3. AUA 2007
!5. NCCN 2016
|-
| rowspan="4" |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
|-
| rowspan="4" |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<sup>[14]</sup> 메타 분석에서 외부 방사선 치료와 장기간 남성 호르몬 박탈요법을 병행한 군이 호르몬 단독 혹은 근접 방사선 치료(brachytherapy) 보다 생존율 향상에 도움이 된다고 보고하였다<sup>[15]</sup>. 최근에는 외부 방사선 치료와 남성 호르몬 박탈요법이 N0M0 병기 뿐만 아니라 N1 병기 환자에서도 이득이 있다는 결과가 보고 되었다<sup>[16,17]</sup>. 

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<sup>[3,18-20]</sup> 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 ==
{| class="wikitable mw-collapsible"
!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
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!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.
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!Study type
|Systematic review and meta-analysis
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!Patients
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!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).
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!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).
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!Level of Study
|1
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