KQ 8. 중간위험 전립선암 환자 중 수술 후 림프절 전이가 있는 환자에서 보조남성호르몬 차단요법은 경과 관찰에 비해 생존율이 높은가?
| 권고사항 | 권고수준 | 근거수준 |
|---|---|---|
| 중간위험 전립선암 환자 중 수술 후 림프절 전이가 있는 환자에서는 보조남성 호르몬 차단요법이 경과 관찰보다 생존율이 높아 보조남성호르몬 차단요법을 권고한다. | A | I |
개요
수술 후 림프절 전이가 있는 환자 중 중간위험 전립선암 환자만을 대상으로 보조남성호르몬 차단요법과 경과 관찰을 비교한 연구는 아직 없다.
보조남성호르몬 차단요법에 관한 연구는 주로 방사선치료에 병행하여 사용된 용법(combination therapy)으로 진행되고 있고 현재까지 근치적전립선절제술 후 시행된 연구는 소수가 발표된 실정이다. 하지만 환자들을 위험도에 따라 분류하지 않고 분석하였거나 고위험 환자와 함께 국소적으로 진행된 전립선암(locally advanced prostate cancer) 환자에 포함하여 분석하였다.
한 무작위 비교연구에서는 국소적으로 진행된 전립선암 환자(T3-4, any N; or any T, N+)에서 보조남성호르몬 차단요법은 무병생존의 연장은 있었으나 전체 생존의 연장은 관찰되지 않았다[1]. 환자의 위험도에 따른 분류 없이 SEER data를 이용한 코호트 연구(cohort study)에서 수술 4개월 이내에 시행한 보조남성호르몬 차단요법은 전체 생존에서의 이점은 없었다[5]. 국내에서 위험도에 따른 분류 없이 근치전립선절제술 후 림프절 전이가 진단된 40명의 환자를 대상으로 한 후향적 연구에서 보조 남성호르몬 박탈요법은 환자의 생존율과 병의 진행을 호전시키지 못하였다[4].
기존 가이드라인 요약 및 수용성, 적용성 평가
수술 후 림프절 전이가 있는 중간위험 전립선암 환자만을 따로 언급한 기존의 진료지침은 없다.
수술 후 림프절 전이가 확인되면 수술 전 임상적 위험도와 상관없이 병리학적 국소진행성암(locally advanced disease)으로 분류하여 언급하고 있다.
EAU guideline과 NCCN guideline, CCAACN guideline에서는 공동으로 하나의 무작위 비교연구 결과를 언급하고 있으나 각각의 권고는 조금씩 다르다. 이들이 공통적으로 언급하고 있는 연구에서는 수술 후 림프절전이가 발견된 환자에 즉각적인 보조 남성호르몬 박탈요법을 시행한 경우 경과 관찰한 군에 비해 생존을 유의하게 연장함을 보였다[2]. 하지만 이 연구에서는 대부분의 참여자들이 다량의 결절성 질환 및 다중 악성 종양의 특징(high-volume nodal disease and multiple adverse tumour characteristics) 등을 가지고 있었고 장기 추적 관찰에서 보조남성호르몬 차단요법의 기간에 따라 부작용도 함께 증가하였다[3]. 따라서 EAU guideline에서는 수술 후 임파선 전이가 있는 환자에 관한 연구들은 매우 이질적인 환자들에 대한 결과로서 일괄적으로 적용하기는 어렵고 그러므로 개별화된 치료가 필요하다고 언급하고 있다. NCCN guideline에서는 수술 후 임파선 전이가 있을 때 보조남성호르몬 차단요법을 반드시 사용하기를 권고하고 있으며 CCAACN guideline에서는 완전하게 제거된 임파선 양성 질환(fully resected node-positive disease)일 경우 생존율에 이점이 있음을 언급하고 있다[2].
NICE guideline에서는 국소진행성암 환자에서 수술 후 보조남성호르몬 차단요법은 독성이 증가하고[6] 효과에 대한 증거 부족으로 권고하지 않는다.
기존 국내 전립선암진료지침에서는 수술 후 림프절전이가 발견된 경우 보조 남성호르몬 박탈요법을 고려할 수 있다고 하였으나 생존율이나 병의 진행에 도움이 되지는 않았다고 언급하고 있다[4,5]
| KQ 8. 중간위험 전립선암 환자 중 수술 후 림프절 전이가 있는 환자에서 보조남성호르몬 차단요법은 경과 관찰에 비해 생존율이 높은가? | ||||
|---|---|---|---|---|
| 지침(제목) | 권고 | 권고등급 | 근거수준 | Page |
| 1. 2015 KUOS | 국내연구결과 생존율을 호전 시키지 못했다(KJU 2011 52 741-5). | 없음 | 없음 | Chap8, 48 |
| 2. EAU 2016 | Upon detection of nodal involvement during RP, Offer adjuvant ADT for node-positive (pN+) | A | 1b | 36 |
| 5. NCCN 2016 | Significantly improved PFS with bicalutamide in the overall study population compared to placebo, but no overall survival benefit was seen. (J Urol 2004 172:1865-70.) | 없음 | 없음 | 45 |
| 6. NICE 2014 | Randomised trials report significant toxicity with adjuvant therapy in addition to radical prostatectomy (Kumar et al. 2006). With the exception of one small trial in node-positive men (Messing et al. 1999), these trials have not demonstrated significant benefit in overall survival. It is possible that modest survival benefits will emerge with longer follow-up. | 없음 | 없음 | 263 |
| 9. CCAACN 2010 | For node-positive disease androgen deprivation therapy (ADT) should be considered. For patients with fully resected node-positive disease (prostatectomy and lymphadenectomy), it is strongly recommended that patients be counselled on the overall survival benefit of ADT and weighed against the short- and longterm toxicities of androgen deprivation. It is further recommended that patients be counselled on the ‘benefit’ of improved survival in relation to the ‘risk’ of therapy - namely the impact of ADT on quality of life. | Grade C | 없음 | 36 |
| 지침(제목) | 1. 2015 KUOS | 2. EAU 2016 | 5. NCCN 2016 | 6. NICE 2014 | 9. CCAACN 2010 | |
|---|---|---|---|---|---|---|
| 수용성 | 인구집단(유병율, 발생율 등)이 유사하다. | 예 | 아니오 | 아니오 | 아니오 | 아니오 |
| 가치와 선호도가 유사하다. | 예 | 예 | 예 | 예 | 예 | |
| 권고로 인한 이득은 유사하다. | 예 | 예 | 예 | 아니오 | 예 | |
| 해당권고는 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 | 예 | 예 | |
NICE 2014 가이드라인은 조금 더 조심스러운 권고를 하고 있으나 타 근거에서 이득이 있음을 보여주고 있어 수용성 평가가 달랐다.
업데이트 근거 요약
중간위험 전립선암 환자 중 수술 후 림프절 전이가 있는 환자에서 보조남성호르몬 차단요법의 이득에 관한 최근 연구는 없는 실정이다.
기존 진료지침에서 따로 다루고 있지는 않지만 최근 여러가지 치료 방법들이 개발되고 적용됨에따라 중간위험 전립선암 환자만을 따로 분류하여 치료할 필요성이 대두되고 있다. 이에 향후 중간위험 환자만을 대상으로 한 잘 계획되고 잘 진행된 전향적 무작위 비교연구가 반드시 필요하겠다.
참고문헌
1. McLeod DG, Iversen P, See WA, Morris T, Armstrong J, Wirth MP. Bicalutamide 150 mg plus standard care vs standard care alone for early prostate cancer. BJU int 2006;97:247-54.
2. 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 nodepositive prostate cancer. N Engl J Med 1999;341:1781-8.
3. 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. Lancet Oncol 2006;7:472-9.
4. 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 J Urol 2011;52:741-5.
5. Wong YN, Freedland S, Egleston B, Hudes G, Schwartz JS, Armstrong K. Role of androgen deprivation therapy for node-positive prostate cancer. J Clin Oncol 2009;27:100-5.
6. Kumar S, Shelley M, Harrison C, Coles B, Wilt T, Mason M. Neo-adjuvant and adjuvant hormone therapy for localised prostate cancer [protocol for a Cochrane review]. Cochrage Database of Systematic Reviews 2006 Issue 2 Chichester (UK): John Wiley & Sons, Ltd.
근거표
| KQ8 | |
|---|---|
| Reference | 1. McLeod DG, Iversen P, See WA, Morris T, Armstrong J, Wirth MP. Bicalutamide 150 mg plus standard care vs standard care alone for early prostate cancer. BJU int 2006;97:247- 54. |
| Study type | Three randomized, double-blind, placebo-controlled trial for combined analysis |
| Patients | 4,052 patients for bicalutamide 150 mg and 4061 to standard care alone |
| Purpose of Study | To evaluate the efficacy and tolerability of bicalutamide 150 mg once daily in addition to standard care for localized or locally advanced, nonmetastatic prostate cancer. |
| Study Results | The large EPC trial programme is defining men who benefit or do not from early or adjuvant antiandrogen therapy. At a median follow-up of 7.4 years, in localized disease there is no benefit to PFS by adding bicalutamide to standard care, and there is a trend (hazard ratio, HR, 1.16; 95% confidence intervals, CI, 0.99-1.37; P=0.07) towards decreased survival in patients otherwise undergoing watchful waiting. However, in locally advanced disease, bicalutamide significantly improved PFS irrespective of standard care. Bicalutamide significantly improved overall survival in patients receiving radiotherapy (HR 0.65; 95% CI 0.44-0.95; P=0.03); this was driven by a lower risk of prostate cancerrelated deaths. Bicalutamide produced a trend towards improved overall survival in patients with locally advanced disease otherwise undergoing watchful waiting (HR 0.81; 95% CI 0.66- 1.01; P=0.06). No survival difference was evident in the prostatectomy subgroup. |
| Level of Study | 1 |
| Reference | 2. 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. N Engl J Med 1999;341:1781-8. |
| Study type | multicenter, randomized controlled trial |
| Patients | 47 patients in the immediate antiandrogen therapy group and 51 patients in the observation group |
| Purpose of Study | To 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 | 3. 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. Lancet Oncol 2006;7:472- 9. |
| Study type | multicenter, randomized controlled trial |
| Patients | 47 patients in the immediate antiandrogen therapy group and 51 patients in the observation group |
| 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 | 4. 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 J Urol 2011;52:741-5. |
| Study type | Retrospective case-control study |
| Patients | 18 patients in ADT group and 22 patients in observation group |
| Purpose of Study | To assessed the role of ADT in disease progression after radical prostatectomy |
| 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 | 5. Wong YN, Freedland S, Egleston B, Hudes G, Schwartz JS, Armstrong K. Role of androgen deprivation therapy for node-positive prostate cancer. J Clin Oncol 2009;27:100- 5. |
| Study type | Cohort study |
| Patients | 209 patients received ADT within 120 days of RP and 522 patients never received ADT |
| 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 | A total of 731 men were identified, 209 of whom received ADT within 120 days of RP. 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 | 2 |