전이성 전립선암 환자의 치료

KQ 17. 전이성 전립선암 환자에서 고환절제술이나 생식샘자극호르몬분비호르몬 작용제를 근간 으로 하는 남성호르몬 박탈요법이 항남성호로몬 제제 단독요법에 비해 생존율을 향상시 킬 수 있는가?

권고사항	권고수준	근거수준
전이성 전립선암 환자에서 고환절제술이나 생식샘자극호르몬분비호르몬 작용제를 근간으로 하는 남성호르몬 박탈요법을 항남성호르몬제제 단독요법보다 우선적으로 권고한다.	B	II

개요

전이성 전립선암 환자에서 남성호르몬 박탈요법은 표준치료방법이다^[1,2]. 남성호르몬 박탈요법은 고환에서의 남성호르몬 분비를 억제하거나 순환 남성호르몬의 수용체에 대한 작용을 억제함으로서 효과를 나타낸다^[1]. 전이성 전립선암 환자에서 표준치료인 남성호르몬 박탈요법에는 여러 가지 방법(생식샘자극호르몬 분비호르몬 작용제(gonadotropin releasing hormone agonist) or GnRH antagonist, 고환절제술, 항남성호르몬제제)이 제시되었지만 어떤 방법이 다른 치료 방법보다 전체 생존율에 있어서 더욱 효과적인지에 대해서는 논란의 여지가 있다. 그러나 여러 연구들은 항남성호르 몬제제 단독요법(antiandrogen monotherapy, bicalutamide 150 mg)이 전이성 전립선암 환자에서 고환절제술이나 남성호르몬 박탈요법과 비교하여 적은 성기능 감소를 보이지만 여성형 유방증의 증가와 전체 생존율의 감소를 보이는 것으로 보고하고 있다^[3-5].

최근 11개의 연구가 포함된 체계적 문헌고찰에서 전이성 전립선암 환자에게 약물학적 또는 외과적 거세와 항남성호르몬제제 단독요법을 비교하였다. 전체 생존율에 있어서 항남성호르몬제제 단독요법이 약물학적 또는 외과적 거세에 비교하여 감소된 생존율을 보였다(hazard ratio 1.24, 95% CI 1.05-1.48). 질환의 임상적 진행에서는 항남성호르몬제제 단독요법이 약물학적 또는 외과적 거세에 비교하여 증가된 결과를 보였다(one year: risk ratio 1.25, 95% CI 1.08-1.45, 70 weeks: risk ratio 1.26, 95% CI 1.08-1.45, two years: risk ratio 1.14, 95% CI 1.04-1.25). 치료의 실패에 있어서도 항 남성호르몬제제 단독요법이 약물학적 또는 외과적 거세에 비교하여 증가된 발생률을 보였다(one year: risk ratio 1.19, 95% CI 1.02-1.38, 70 weeks: risk ratio 1.26, 95% CI 1.08-1.45, two years: risk ratio 1.14, 95% CI 1.05-1.24)^[5,6]. 또한 다른 메타 분석에서는 전이성 전립선암 환자에서 항남 성호르몬제제 단독요법이 고환절제술 또는 남성호르몬 박탈요법보다 더 낮은 전체 생존율을 보였다 (hazard ratio 1.2158, CI 0.988-1.496). 남성호르몬 박탈요법은 고환절제술에 비교하여 전체 생존율 에서 별다른 차이를 보이지 않았다(hazard ratio 1.1262, CI 0.915-1.386)^[3].

기존 가이드라인 요약 및 수용성, 적용성 평가

2016년 EAU (European Association of Urology) 가이드라인에서는 전이성 전립선암 환자에게 약물학적 또는 외과적 거세와 비교한 항남성호르몬제제 단독요법은 전체 생존율, 질환의 임상적 진행, 치료 실패 그리고 부작용 발생으로 인한 치료중단에 있어서 덜 효과적이라고 분석한 최근의 체계적 문헌고찰을 근거로 전이성 전립선암 환자에게 항남성호르몬제제 단독요법을 시행하지 않도록 권고하고 있다^[5]. 2016년 NCCN (National Comprehensive Cancer Network) 가이드라인에서는 항남성호르몬제제 단독요법이 전이성 전립선암 환자에서 고환절제술 또는 남성호르몬 박탈요법보다 전체 생존율, 질환의 임상적 진행 그리고 치료 실패에 대한 효과가 적어 주요 남성호르몬 박탈 요법으로 권고하고 있지 않았다^[5,7]. 2014년 NICE (National Institute for Health and Care Excellence) 가이드라인에서는 전이성 전립선암 환자에서 여성형유방증은 항남성호르몬제제 단독요법에서 안면홍조와 감소된 성기능은 고환절제술 또는 남성호르몬 박탈요법에서 더 흔하게 나타나지만 전체 생존율에 있어서는 항남성호르몬제제 단독요법이 고환절제술 또는 남성호르몬 박탈요법보다 좋지 않음을 보고한 메타 분석과 여러 연구 결과를 근거로 제시하고 있다. 이를 종합하여 성기능을 유지하기 원하고 여성형 유방증과 전체 생존율에 대한 부작용을 기꺼이 받아들일 수 있는 전이성 전립선암 환자에게 항남성호르몬제제 단독요법(bicalutamide 150 mg)을 투약할 수 있다고 하였다. 이러한 경우라도 항남성호르몬제제 단독요법 중 만족스러운 성기능 유지가 되지 않는 환자에서는 bicalutamide 투약 을 중단하고 다른 남성호르몬 박탈요법을 시행할 것을 권고하고 있다^[3,8,9]. 2010년 CCAACN (Cancer Council Australia/Australian Cancer Network) 가이드라인에서는 전이성 전립선암 환자에게 고환절제술과 항남성호르몬제제 단독요법을 시행하여 두 군 사이에서 평균 치료의 실패 시기(치료 시작 후 419 vs 496 days, p=0.32)와 평균 질환의 임상적 진행(370 vs 396 days, p=0.9)에서 별다른 차이를 보이지 않았고 전체 생존율은 치료방법에 상관없이 69개월을 보인 연구를 근거로 전이성 전립선암 환자에게 환자의 선택에 따라 고환절제술이나 남성호르몬 박탈요법으로 치료를 시작할 것을 권고하고 있었다. 또한 합병증에 있어서는 전이성 전립선암 환자에서 여성형유방증은 항남성호르몬제제 단독 요법에서 좀더 많이 나타나고 안면홍조와 감소된 성기능은 고환절제술 또는 남성호르몬 박탈요법에서 더 흔하게 나타나지만 전체 생존율에 있어서는 항남성호르몬제제 단독요법이 고환절제술 또는 남 성호르몬 박탈요법보다 좋지 않음을 제시한 메타 분석 결과를 근거로 항남성호르몬제제 단독요법은 전체 생존율이 낮아서 추천하지 않는다^[3,4,10].

KQ 17. 전이성 전립선암 환자에서 고환절제술이나 생식샘자극호르몬분비호르몬 작용제를 근간으로 하는 남성호르몬 박탈 요법이 항남성호로몬 제제 단독요법에 비해 생존율을 향상시킬 수 있는가?
지침(제목)	권고	권고등급	근거수준	page
2. EAU 2016	Do not offer anti-androgen monotherapy in M1 patients.	A	1a	57
5. NCCN 2016	Antiandrogen monotherapy appears to be less effective than medical or surgical castration and is not recommended.	B	1b	30
6. NICE 2014	For men with metastatic prostate cancer who are willing to accept the adverse impact on overall survival and gynaecomastia in the hope of retaining sexual function, offer anti-androgen monotherapy with bicalutamide (150 mg).	A	1a	353
9. CCAACN 2010	Patients with metastatic prostate cancer can be treated with either orchidectomy or LHRH agonist based on patient preference. Anti-androgen monotherapy should be avoided as the data indicate this is probably associated with a shorter overall survival.	C	2	51

지침(제목)		2. EAU 2016	5. NCCN 2016	6. NICE 2014	9. CCAACN 2010
수용성	인구 집단(유병률, 발생률 등)이 유사하다.	예	예	불확실	예
	가치와 선호도가 유사하다.	예	예	예	예
	권고로 인한 이득은 유사하다.	예	예	예	예
	해당 권고는 수용할 만하다.	예	예	불확실	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 적용할 만하다.	예	예	예	예

업데이트 근거 요약

전이성 전립선암 환자에서 표준치료인 남성호르몬 박탈 요법 중 고환절제술과 LHRH agonist 또는 antagonist 사이에서 어떤 치료 방법이 더욱 효과적인지에 대해서는 아직 논란의 여지가 있다. 전립선암을 조절하는 면에서 두 방법은 비슷한 효과를 보이는 것으로 알려져 있다. 2016년에 Sun M 등 은 전이성 전립선암으로 진단된 3,295명의 환자 중 고환절제술을 시행 받은 429명과 LHRH agonist을 투여 받은 2,866명을 대상으로 치료 부작용을 비교하였다. 고환절제술을 받은 군에 비하여 LHRH agonist을 투여 받은 환자들에서 골절(HR 1.80), 말초 동맥 질환(HR 2.25), 정맥 혈전증(HR 1.52), 심혈관 관련 부작용(HR 1.69), 그리고 당뇨(HR 1.52)의 위험성이 높음을 제시하였다(P<0.01)^[11]. 그러나 2017년에 Chen DY 등은 전립선암으로 진단된 14,715명의 환자 중 고환절제술을 시행 받은 3,578명과 LHRH agonist을 투여 받은 11,137명을 대상으로 심혈관 부작용을 비교하여 두 군사이에 심혈관 부작용의 발생에는 유의한 차이를 보이지 않았으나(HR 1.16, P=0.09) LHRH agonist을 투여 받은 군에 비하여 고환절제술을 시행 받은 군에서 1.5년 이내에 심혈관 부작용 발생의 경향이 증가했다고 보고하였다(HR 1.4, P=0.027)^[12].

향후 전이성 전립선암 환자에게 있어 약물학적 또는 외과적 거세, 항남성호르몬제제 단독요법을 이용한 장기적 추적 관찰이 포함된 잘 계획된 무작위 대조군 연구가 필요할 것으로 생각된다. 이 연구에는 현재의 가이드라인에 기초한 주기적인 PSA 측정이 포함된 전이성 전립선암의 생화학적 진행에 중점을 두어야 하겠다.

참고문헌

1. Pagliarulo V, Bracarda S, Eisenberger MA, et al. Contemporary role of androgen deprivation therapy for prostate cancer. Eur Urol 2012;61:11-25.

2. Loblaw DA, Virgo KS, Nam R, 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. J Clin Oncol 2007;25:1596-605.

3. Seidenfeld J, Samson DJ, Hasselblad V, et al. Single-therapy androgen suppression in men with advanced prostate cancer: a systematic review and meta-analysis. Ann Intern Med 2000;132:566-77.

4. Schroder FH, Whelan P, de Reijke TM, et al. Metastatic prostate cancer treated by flutamide versus cyproterone acetate. Final analysis of the “European Organization for Research and Treatment of Cancer” (EORTC) Protocol 30892. Eur Urol 2004;45:457-64.

5. Kunath F, Grobe HR, Rucker G, et al. Non-steroidal antiandrogen monotherapy compared with luteinising hormone-releasing hormone agonists or surgical castration monotherapy for advanced prostate cancer. Cochrane Database Syst Rev 2014:CD009266.

6. Kunath F, Grobe HR, Rucker G et al. Non-steroidal antiandrogen monotherapy compared with luteinizing hormone-releasing hormone agonists or surgical castration monotherapy for advanced prostate cancer: a Cochrane systematic review. BJU Int 2015;116:30-6.

7. Wirth MP, Hakenberg OW, Froehner M. Antiandrogens in the treatment of prostate cancer. Eur Urol 2007;51:306-13;discussion 14.

8. Raina R, Pahalajani G, Agarwal A, Zippe C. Long-term effectiveness of luteinizing hormone-releasing hormone agonist or antiandrogen monotherapy in elderly men with localized prostate cancer (T1-2): a retrospective study. Asian J Androl 2007;9:253-8.

9. Wadhwa VK, Weston R, Parr NJ. Bicalutamide monotherapy preserves bone mineral density, muscle strength and has significant health-related quality of life benefits for osteoporotic men with prostate cancer. BJU Int 2011;107:1923-9.

10. Boccon-Gibod L, Fournier G, Bottet P, et al. Flutamide versus orchidectomy in the treatment of metastatic prostate carcinoma. Eur Urol 1997;32:391-5;discussion 5-6.

11. Sun M, Choueiri TK, Hamnvik OP, et al. Comparison of Gonadotropin-Releasing Hormone Agonists and Orchiectomy: Effects of Androgen-Deprivation Therapy. JAMA Oncol 2016;2:500-7.

12. Chen DY, See LC, Liu JR, et al. Risk of Cardiovascular Ischemic Events After Surgical Castration and Gonadotropin-Releasing Hormone Agonist Therapy for Prostate Cancer: A Nationwide Cohort Study. J Clin Oncol 2017;35:3697-705.

근거표

KQ17
Reference	1. Pagliarulo V, Bracarda S, Eisenberger MA et al. Contemporary role of androgen deprivation therapy for prostate cancer. Eur Urol 2012;61:11-25.
Study type	Systematic review
Patients	48 studies
Purpose of Study	To evaluate whether adding short-term ADT to radiotherapy would improve survival among patients with nonbulky localized prostate adenocarcinomas and an initial PSA level of 20 ng per milliliter or less.
Study Results	Data from randomized controlled trials and population-based studies were analyzed in different clinical paradigms. Specifically, the role of ADT was evaluated in patients with nonmetastatic disease as the primary and sole treatment, in combination with radiation therapy (RT) or after surgery, and in patients with metastatic disease. The data suggest that in men with nonmetastatic disease, the use of primary ADT as monotherapy has not shown a benefit and is not recommended, while ADT combined with conventional-dose RT (<72Gy) for patients with high-risk disease may delay progression and prolong survival. The postoperative use of ADT remains poorly evaluated in prospective studies. Likewise, there are no trials evaluating the role of ADT in patients with biochemical relapses after surgery or RT. In patients with metastatic disease, there is a clear benefit in terms of quality of life, reduction of disease-associated morbidity, and possibly survival. Treatment with bilateral orchiectomy, luteinizing hormone-releasing hormone agonist therapy, with and without antiandrogens has been associated with various serious adverse events, including cardiovascular disease, diabetes, and skeletal complications that may also affect mortality.
Level of Study	1
Reference	2. Kunath F, Grobe HR, Rucker G, et al. Non-steroidal antiandrogen monotherapy compared with luteinising hormone-releasing hormone agonists or surgical castration monotherapy for advanced prostate cancer. Cochrane Database Syst Rev 2014:CD009266.
Study type	Systematic review
Patients	11 studies, 3,060 patients
Purpose of Study	To assess the effects of non-steroidal antiandrogen monotherapy compared with luteinising hormone-releasing hormone agonists or surgical castration monotherapy for treating advanced stages of prostate cancer.
Study Results	Eleven studies involving 3060 randomly assigned participants were included in this review. The quality of evidence is hampered by risk of bias. Use of non-steroidal antiandrogens decreased overall survival (hazard ratio (HR) 1.24, 95% confidence interval (CI) 1.05 to 1.48, six studies, 2712 participants) and increased clinical progression (one year: risk ratio (RR) 1.25, 95% CI 1.08 to 1.45, five studies, 2067 participants; 70 weeks: RR 1.26, 95% CI 1.08 to 1.45, six studies, 2373 participants; two years: RR 1.14, 95% CI 1.04 to 1.25, three studies, 1336 participants), as well as treatment failure (one year: RR 1.19, 95% CI 1.02 to 1.38, four studies, 1539 participants; 70 weeks: RR 1.27, 95% CI 1.05 to 1.52, five studies, 1845 participants; two years: RR 1.14, 95% CI 1.05 to 1.24, two studies, 808 participants), compared with medical or surgical castration. The quality of evidence for overall survival, clinical progression and treatment failure was rated as moderate according to GRADE. Predefined subgroup analyses showed that use of non-steroidal antiandrogens, compared with castration, was less favourable for overall survival, clinical progression (at one year, 70 weeks, two years) and treatment failure (at one year, 70 weeks, two years) in men with metastatic disease. Use of non-steroidal antiandrogens also increased the risk for treatment discontinuation due to adverse events (RR 1.82, 95% CI 1.13 to 2.94, eight studies, 1559 participants), including events such as breast pain (RR 22.97, 95% CI 14.79 to 35.67, eight studies, 2670 participants), gynaecomastia (RR 8.43, 95% CI 3.19 to 22.28, nine studies, 2774 participants) and asthenia (RR 1.77, 95% CI 1.36 to 2.31, five studies, 2073 participants). The risk of other adverse events, such as hot flashes (RR 0.23, 95% CI 0.19 to 0.27, nine studies, 2774 participants), haemorrhage (RR 0.07, 95% CI 0.01 to 0.54, two studies, 546 participants), nocturia (RR 0.38, 95% CI 0.20 to 0.69, one study, 480 participants), fatigue (RR 0.52, 95% CI 0.31 to 0.88, one study, 51 participants), loss of sexual interest (RR 0.50, 95% CI 0.30 to 0.83, one study, 51 participants) and urinary frequency (RR 0.22, 95% CI 0.11 to 0.47, one study, 480 participants) was decreased when non-steroidal antiandrogens were used. The quality of evidence for breast pain, gynaecomastia and hot flashes was rated as moderate according to GRADE. The effects of non-steroidal antiandrogens on cancer-specific survival and biochemical progression remained unclear.
Level of Study	1
Reference	3. Seidenfeld J, Samson DJ, Hasselblad V et al. Single-therapy androgen suppression in men with advanced prostate cancer: a systematic review and meta-analysis. Ann Intern Med 2000;132:566-77.
Study type	Meta-analysis
Patients	10 studies, 1,908 patients
Purpose of Study	To compare luteinizing hormone-releasing hormone (LHRH) agonists with orchiectomy or diethylstilbestrol, and to compare antiandrogens with any of these three alternatives.
Study Results	Ten trials of LHRH agonists involving 1908 patients reported no significant difference in overall survival. The hazard ratio showed LHRH agonists to be essentially equivalent to orchiectomy (hazard ratio, 1.1262 [corrected] [95% CI, 0.915 to 1.386]). There was no evidence of difference in overall survival among the LHRH agonists, although CIs were wider for leuprolide (hazard ratio, 1.0994 [CI, 0.207 to 5.835]) and buserelin (hazard ratio, 1.1315 [CI, 0.533 to 2.404]) than for goserelin (hazard ratio, 1.1172 [CI, 0.898 to 1.390]). Evidence from 8 trials involving 2717 patients suggests that nonsteroidal antiandrogens were associated with lower overall survival. The CI for the hazard ratio approached statistical significance (hazard ratio, 1.2158 [CI, 0.988 to 1.496]). Treatment withdrawals were less frequent with LHRH agonists (0% to 4%) than with nonsteroidal antiandrogens (4% to 10%).
Level of Study	1
Reference	4. Sun M, Choueiri TK, Hamnvik OP, et al. Comparison of Gonadotropin-Releasing Hormone Agonists and Orchiectomy: Effects of Androgen-Deprivation Therapy. JAMA Oncol 2016;2:500-7.
Study type	Case-control study
Patients	A population-based cohort of 3,295 men with metastatic PCa between January 1995 and December 2009 66 years or older was selected from the Surveillance, Epidemiology, and End Results (SEER) Medicare-linked database
Purpose of Study	To provide a comparative effectiveness analysis of the adverse effects of gonadotropin- releasing hormone agonists (GnRHa) vs bilateral orchiectomy in a homogeneous population.
Study Results	Overall, 3295 men with a primary diagnosis of metastatic PCa treated with GnRHa or orchiectomy were identified between years 1995 and 2009, and in adjusted analyses, patients who received a bilateral orchiectomy had significantly lower risks of experiencing any fractures (hazard ratio [HR], 0.77; 95% CI, 0.62-0.94; P=.01), peripheral arterial disease (HR, 0.65; 95% CI, 0.49-0.87; P=.004), and cardiac-related complications (HR, 0.74; 0.58-0.94; P=.01) compared with those treated with GnRHa. No statistically significant difference was noted between orchiectomy and GnRHa for diabetes and cognitive disorders. In individuals treated with GnRHa for 35 months or more, the increased risk for GnRHa compared with orchiectomy was noted for fractures (HR, 1.80), peripheral arterial disease (HR, 2.25), venous thromboembolism (HR, 1.52), cardiac-related complications (HR, 1.69), and diabetes mellitus (HR, 1.88) (P≤.01 for all). At 12 months after PCa diagnosis, the median total expenditures was not significantly different between GnRHa and orchiectomy.
Level of Study	3
Reference	5. Chen DY, See LC, Liu JR, et al. Risk of Cardiovascular Ischemic Events After Surgical Castration and Gonadotropin-Releasing Hormone Agonist Therapy for Prostate Cancer: A Nationwide Cohort Study. J Clin Oncol 2017;35:3697-705.
Study type	Case-control study
Patients	By using the Taiwan National Health Insurance Research Database, we analyzed data from 14,715 patients with PCa diagnosed from January 1, 1997, through December 31, 2011
Purpose of Study	Our aim was to determine whether cardiovascular (CV) risk in patients with prostate cancer (PCa) differs between those who receive androgen-deprivation therapy by surgical castration and those who receive gonadotropin-releasing hormone agonist (GnRHa) therapy.
Study Results	Overall, 3,578 patients with PCa (24.3%) underwent bilateral orchiectomy and 11,137 patients (75.7%) received GnRHa therapy. Both groups had a similar risk of CV ischemic events (ie, MI or IS; hazard ratio, 1.16; 95% CI, 0.97 to 1.38) during a median follow- up time of 3.3 years. However, during the first 1.5 years of follow-up, there were higher CV ischemic events in the orchiectomy group than in the GnRHa group (hazard ratio, 1.40; 95% CI, 1.04 to 1.88), particularly in patients who were ≥65 years of age, had hypertension, had a Charlson comorbidity index score ≥3, and had a previous history of MI, IS, or coronary heart disease. Conclusion Compared with bilateral orchiectomy, use of GnRHa does not increase the risk of CV ischemic events in patients with PCa. Nonetheless, orchiectomy is associated with higher rates of CV ischemic events in older patients and those with a history of CV comorbidities within 1.5 years of initiating androgen-deprivation therapy. These findings can help clinicians decide on the optimal castration strategy for individual patients.
Level of Study	3