臺灣攝護腺癌專家共識 Taiwan Advanced Prostate Cancer Consensus

(1)

第二部分

Treatment Recommendation

評論分析：莊正鏗

Cancer Consensus

局部侵犯性攝護腺癌

Locally Advanced Prostate Cancer

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For patients with a life expectancy of 5-10 years, ECOG PS 0-1, no significant co-morbidities, DRE T2c, iPSA 21, biopsy Gleason 7, MRI: suspected seminal vesicle invasion (T3b), and negative bone scan, which of the followings do you most recommend? (單選)

【選項】左側紅色數字為第一輪所有專家通訊投票之結果 7% 1. Radical prostatectomy alone

2% 2. Neoadjuvant ADT followed by radical prostatectomy 8% 3. Radical prostatectomy followed by adjuvant RT 9% 4. Radiotherapy with short-term (~6 months) ADT 68% 5. Radiotherapy with long-term (18~36 months) ADT 2% 6. Radiotherapy with life-long ADT

0% 7. Chemotherapy ＋ Radiotherapy ＋ ADT 0% 8. Chemohormonal therapy

1% 9. Cryoablation ± ADT 0% 10. HIFU ± ADT

0% 11. Primary life-long ADT only 2% 12. Watchful waiting

1% X. Abstain (棄權，不表示意見)

Y. Unqualified to answer (平常臨床業務，不處理此類病人)

【第二輪結果】

•評論分析：

選項

5

所有專家 (N=46)

84%

泌尿科醫師 (N=33)

78%

放射腫瘤科醫師 (N=12)

100%

高治療量醫師 (N=33)

82%

資深醫師 (N=25)

80%

38

子題2-1

根據NCCN guideline以及其他臨床證據，對於cT3b的患者，大部分專家認為應給予radia- tion併長期ADT; 約兩成的泌尿科醫師認為某些病患可以考慮手術治療。2016 EAU guide- line對於LAPC的治療建議是，針對無法或是不願接受任何形式局部治療的病患，如果PSA doubling time 超過一年， PSA ＜ 50 ng/mL，且沒有high Gleason grade也無症狀，可以先使用ADT monotherapy，未來如有需要可以進行後續追加的治療(deferred therapy)。

然而有與會專家提出，題目中的病患只有5~10年的平均餘命，可以想像成約80~85歲的老人，是否還需要進行手術或放療等積極性治療?若選擇ADT或watchful waiting是否也是一個合理的選擇?Clinical Practice Guideline for Prostate Cancer Treatment對於LAPC的治療給了相當詳細的建議: life expectancy超過10年的LAPC，建議放射線治療；如果淋巴結侵犯的機會不高者(cT3a ＋ Gleason ＜ 8 ＋ PSA ＜ 20 ng/ml)，可以考慮手術治療；如果life expectancy小於10年，那麼watchful waiting或是荷爾蒙治療都是選擇。

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1. NCCN guideline version 2016

2. Clinical Practice Guideline for Prostate Cancer Treatment

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40

For patients with a life expectancy ＜5 years, ECOG PS 0-1, no significant co-morbidities, DRE T2c, iPSA 21 ng/ml, biopsy Gleason 7, MRI: suspected seminal vesicle invasion (T3b), and negative bone scan, which of the followings do you most recommend? (單選)

【選項】

0% 1. Radical prostatectomy alone

•評論分析：

•參考資料：

子題2-2

選項 5 11 12

所有專家 (N=46)

64%

22%

11%

53%

31%

16%

92%

0%

70%

15%

12%

資深醫師 (N=25)

60%

24%

12%

此一議題則是對於預期餘命小於五年且cT3b病患的治療選擇，結果可以放射線腫瘤科醫師大多數採取長期荷爾蒙治療加上放射治療，而泌尿科醫師多不再建議手術治療，有一半會建議放射治療，而其他三、四成的泌尿科醫師則選擇了荷爾蒙治療，或是追蹤觀察。

Clinical Practice Guideline for Prostate Cancer Treatment

In patients with prostate cancer at the locally advanced clinical stage with a life expectancy below 10 years, watchful waiting or hormone therapy may be therapeutic alternatives.

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選項 1 2

所有專家 (N=46)

84%

9%

81%

13%

100%

0%

82%

12%

資深醫師 (N=25)

76%

12%

對於 life expectancy 僅有5年的very high risk (GS 9，cT3b) 病患，與會專家們多採取比上一題選擇更積極的局部治療方法。例如：放射線腫瘤科醫師都建議長期荷爾蒙治療＋放射治療，而超過八成的泌尿科醫師也選擇了相同的建議。僅有約一成的泌尿科醫師建議給予較保守的荷爾蒙治療或是追蹤觀察。Peter Grimm et al曾經分析了從2000-2011年發表的文章，超過52,000個不同risk groups接受primary therapy的結果。High risk group的病人，

以multimodality treatment比montherapy有較好的progression-free survival，但是並無overall survival之分析結果可供比較。最重要的是目前也無針對預期餘命短的LAPC病人的隨機試驗，可供評估何種治療對於病人較有利。

How do you identify locally advanced prostate cancer? Suppose you already have the DRE findings, PSA, and biopsy Gleason score and patients are considering observation or primary ADT due to short life expectancy/co-morbidities. What do you do next for workup? (單選)

【選項】

•評論分析：

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42

Comparative analysis of prostate-specific antigen free survival outcomes for patients with low, intermediate and high risk prostate cancer treatment by radical therapy. Results from the Pros- tate Cancer Results Study Group. BJU International 2012, 109; sup 1, 22-29

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選項 1 5

所有專家 (N=46)

80%

16%

97%

0%

33%

58%

76%

21%

資深醫師 (N=25)

84%

8%

根據NCCN guideline以及其他臨床證據，對於cT3a的病人，大部分專家認為應給予長期荷爾蒙治療以及放射治療。雖然如此，EORTC-30001的研究中，有43.8%的cT3病人，手術後實際上是organ-confined的。因此，部分經選擇的病人中，radical surgery也是很好的選擇。 Clinical Practice Guideline for Prostate Cancer Treatment對於整個LAPC的治療建議給了相當詳細的建議: life expectancy超過10年者，建議放射線治療；如果淋巴結侵犯的機會不高者 (cT3a ＋ Gleason ＜ 8 ＋ PSA ＜ 20 ng/ml)，可以考慮手術治療。所以我們絕大多數與會的泌尿科醫師，都選擇手術治療，也有高達四成的放射線腫瘤醫師建議手術治療。

For patients with a life expectancy ＞15 years, ECOG PS 0, no significant co-morbidities, DRE T2c, PSA 21 ng/ml, biopsy Gleason ≦ 7, MRI: suspected extracapsular extension (T3a), and negative bone scan, which of the followings do you most recommend? (單選)

【選項】

0% 7. Chemotherapy c Radiotherapy ＋ ADT 0% 8. Chemohormonal therapy

•評論分析：

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44

1. Radical prostatectomy for locally advanced prostate cancer: current status. Urology 86:10-15, 2015.

2. Clinical Practice Guideline for Prostate Cancer Treatment

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選項 2 3

所有專家 (N=46)

22%

78%

31%

69%

0%

100%

24%

76%

資深醫師 (N=25)

24%

76%

對於較長預期餘命的病人，即使是cT4或是high Gleason score，仍有約三成的泌尿科醫師傾向於施行手術治療，放射線腫瘤醫師則是一致建議放射線治療加上長期荷爾蒙治療。

Peter A.S. Johnstone et al在Cancer 發表針對SEER data 1995-2001七年當中的1093個cT4、

lymph-node negative or lymph-node positive、且 M0病人，於2002年分析他們接受不同治療追蹤的資料，結果發現接受radical prostatectomy (72個病患, 6.6%) 的存活率最好，沒有治療的最差。接受radical prostatectomy的病人存活率與放射線治療加上荷爾蒙治療的效果相近。 NCCN guideline 2015也建議在部分選擇過的病人，可以考慮施行radical prostatec- tomy加上pelvic lymph node dissection。

For patients with a cT4N0M0 disease, a life-expectancy of 10~15 years, iPSA 30 ng/ml, Gleason 4＋5, which of the followings do you recommend? (單選)

【選項】

4% 1. Radical surgery ± ADT (may include cystoprostatectomy)

19% 2. Radical surgery ＋ adjuvant EBRT ± ADT (may include cystoprostatectomy) 64% 3. External beam radiotherapy (EBRT) ± ADT

4% 8. Primary continuous ADT 0% 9. Primary intermittent ADT 0% 10. Watchful waiting

•評論分析：

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46

1. Radical prostatectomy for clinical T4 prostate cancer. Cancer 2006;106:2603-9 2. EAU guideline 2015

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選項 2 3

所有專家 (N=46)

16%

80%

22%

72%

0%

100%

18%

79%

資深醫師 (N=25)

24%

76%

對於N1的病人，絕大多數專家都建議放射線治療加上荷爾蒙治療，基本上是遵循了NCCN guidelines的建議。然而，也有約兩成的泌尿科醫師會考慮手術以及後續的放射治療與荷爾蒙治療。Engel et al 回溯性研究發現radical prostatectomy對於N1病人，仍有治療的價值，

其overall survival在有施行radical prostatectomy高於未施行者(5年84 vs 64%, 10年60 vs 28%)。Gakis et al回顧1993-2012接受radical prostatectomy的N1 病患的發表文獻，發現 radical prostatectomy可以增加progression-free survival與overall survival。但截至目前為止，

並無randomized trial可供參閱與證實。

For patients with a cT3N1M0 disease, a life-expectancy of 10~15 years, iPSA 30 ng/ml, Gleason 4＋5, which of the followings do you recommend? (單選)

【選項】

6% 1. Radical prostatectomy ＋ pelvic LN dissection (PLND) 17% 2. Radical prostatectomy ＋ PLND ＋ ADT

63% 3. External beam radiotherapy (EBRT) ＋ ADT 5% 4. Radical prostatectomy ＋ adjuvant EBRT ± ADT 4% 5. Chemotherapy ＋ Radiotherapy + ADT

0% 6. Chemohormonal therapy 0% 7. Cryoablation ± ADT 1% 8. HIFU ± ADT

3% 9. Primary continuous ADT 0% 10. Primary intermittent ADT 0% 11. Watchful waiting

•評論分析：

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48

1. Survival benefit of radical prostatectomy in lymph node-positive patients with prostate cancer.　Eur Urol. 2010 May;57(5):754-61.

2. The role of radical prostatectomy and lymph node dissection in lymph node-positive prostate cancer: a systematic review of the literature.　Eur Urol. 2014 Aug;66(2):191-9.

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術前影像檢查有高度懷疑癌症侵犯neurovascular bundle者，絕大多數醫師都不建議施行該側神經保留手術。2016 EAU guideline 針對神經保留手術，建議任何有高度風險pT3的狀況「例如any cT2c or cT3, any GS ＞ 7 on biopsy」，不適宜施行神經保留手術。目前，可以使用nomogram預測extracapsular extension,也可以利用multiparametric MRI選擇神經保留的手術進行方式。如有任何可能會由殘餘腫瘤的疑慮，醫師應該施行神經血管叢的切除

。此外，術中的frozen biopsy，也可以提供手術醫師做是否保留神經的依據。

During planning for radical prostatectomy, under which of the following conditions do you NOT recommend ipsilateral neurovascular bundle (NVB) preservation? (複選)

【選項】

72% 1. DRE showed a T3a lesion invading the extra-prostatic space postero-laterally. The lesion was proved to be cancer by biopsy.

29% 2. DRE showed a T2b lesion at the posterolateral aspect of the prostate. The lesion was proved to be cancer by biopsy.

68% 3. MRI showed ipsilateral NVB invasion

4% 4. MRI showed ipsilateral tumor lesion but no evident NVB invasion

6% 5. Ipsilateral high Gleason score (eg. 4＋4＝8) tumor, irrespective of DRE or MRI findings.

28% 6. Ipsilateral high Gleason score (eg. 4＋4＝8) tumor, along with DRE or MRI findings showing T2b lesion

14% 7. Depending on frozen pathology of a piece of NVB tissue during prostatectomy 1% 8. I always do NVB preservation no matter what conditions.

1% 9. I never do NVB preservation no matter what conditions 7% X. Abstain (棄權，不表示意見)

•評論分析：

選項 1 2 3 6

所有專家 (N=46)

94%

27%

82%

12%

97%

28%

81%

13%

0%

95%

24%

86%

14%

資深醫師 (N=25)

95%

42%

32%

16%

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50

2016 EAU Guideline

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For patients with a life-expectancy of ＜10 years (eg. age ＞78 years), taking anti-coagulants, and with a high-risk disease (cT3aN0M0, iPSA 25, GS 4＋4＝8), which of the followings do you recommend? (單選)

【選項】

45% 1. Give ≧ 75.6 Gy RT dose ± ADT, if dose distribution meets the rectal and bladder constraints, despite short life-expectancy.

6% 2. Give < 75.6 Gy RT ± ADT due to short life-expectancy, even though the dose distribution meets the rectal and bladder constraints.

18% 3. Only primary ADT.

1% 4. Only watchful waiting.

1% 5. Energy ablation ± ADT 1% 6. None of the above

“Dose” means DVH: dose –volume histogram

•評論分析：

絕大多數放射腫瘤科專家，認為以現在的放射線治療技術以及dose-volume histogram anal- ysis的應用，即使病人的預期餘命較短而且使用抗凝血劑，仍建議以＞75.6 Gy劑量進行攝護腺放射線治療。Kevin S. Choe et al. 曾報告1988至2005年的568接受放射線治療的病患，

在追蹤48個月後，使用抗凝血劑的病人發生grade 3 以上的bleeding toxicity(15.5%)高於未使用者(3.6%)。多變性分析中，使用抗凝血劑是唯一造成出血的因素。以dose-volume histogram分析，如果直腸照射劑量超過70 Gy的所佔的部分<10%或是直腸照射超過50 Gy 的不超過一半，那麼發生嚴重出血的機會就下降。

選項 1 2 3 4

所有專家 (N=46)

66%

11%

14%

7%

58%

10%

19%

10%

83%

17%

0%

72%

13%

6%

資深醫師 (N=25)

68%

4%

16%

12%

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52

External beam radiotherapy for prostate cancer patients on anticoagulation therapy: how significant is the bleeding toxicity? Int. J. Radiation Oncology Biol. Phys. 2010, 76; 3: 755-60

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選項 1 2

所有專家 (N=46)

75%

17%

70%

17%

83%

17%

77%

19%

資深醫師 (N=25)

81%

5%

此題與上一題一樣，不過在這題主要在於選擇放射劑量，無論是泌尿科或放射腫瘤科醫師均傾向，在dose-volume histogram分析應用下，對於very high risk的病人，即使預期餘命小於10年，仍建議選擇高劑量的照射。

For patients with a life-expectancy of ＜10 years (eg. age ＞80 years), taking anti-coagulants, and with a high-risk disease (cT3aN0M0, iPSA 25, GS 4＋4＝8), who chooses to undergo definitive EBRT, which of the followings do you recommend? (單選)

【選項】

58% 1. Give ≧ 75.6 Gy RT dose ± ADT, if dose distribution meets the rectal and bladder constraints, despite short life-expectancy.

33% 2. Give < 75.6 Gy RT ± ADT due to short life-expectancy, even though the dose distribution meets the rectal and bladder constraints.

•評論分析：

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54

子題2-11

絕大多數專家均同意，即使病人有較短的預期餘命，仍應選擇長期的ADT治療。Eric M.

Horwitz 於2009 JCO報告了RTG 92-02試驗，針對T2c-4N0-x且 PSA ＜ 150 ng/mL的病人，

接受放射線治療的同時使用4個月或是24個月ADT。兩組平均追蹤均超過11年，Gleason score 8-10的病人中，24個月ADT較4個月ADT的病人在disease-free、 disease-specific 及 overall survival等項目較佳。

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. JCO 2008, 26;

15:2497-2504

*

Regarding adjuvant ADT, which of the followings do you recommend for patients described in Q2-10? (單選)

【選項】

3% 1. Withhold adjuvant ADT due to short life-expectancy 29% 2. Give a short-term ADT due to short life-expectancy 64% 3. Give a long-term ADT despite short life-expectancy 1% 4. None of the above

•評論分析：

•參考資料：

選項 3

所有專家 (N=46)

93%

90%

100%

資深醫師 (N=25)

92%

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選項 3 4

所有專家 (N=46)

74%

8%

77%

0%

67%

25%

73%

10%

資深醫師 (N=25)

70%

9%

多數醫師尤其是絕大多數的放射腫瘤科醫師都同意在施行放射線治療時，如果有懷疑淋巴侵犯時，不論是影像上或是以normogram計算出來，都會包括骨盆腔放射線照射。

Under which of the following conditions do you recommend RT to the pelvic nodes in addi- tion to RT to the prostate/seminal vesicles? (單選)

【選項】

20% 1. Suspicious pelvic LAP by images

7% 2. Suspicious pelvic LAP by algorithms or nomograms, if LN mets probability is high 40% 3. Either 1 or 2

21% 4. Both 1 and 2

4% 5. All cases with clinical T3/T4 diseases 2% 6. Never give pelvic node irradiation 0% 7. None of the above

•評論分析：

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56

For patients with LAPC who are counseled about radical prostatectomy, which of the followings concerns you most? (單選)

【選項】

2% 1. Erectile dysfunction 26% 2. Urinary incontinence 11% 3. Positive surgical margin 60% 4. Disease (cancer) control 0% 5. None of the above

•評論分析：

•參考資料：

選項

2 3 4

所有專家 (N=46)

25%

8%

68%

25%

3%

72%

29%

14%

57%

36%

7%

57%

資深醫師 (N=25)

26%

9%

65%

癌症控制一直都是癌症治療的終極目標，當然相關的併發症也是醫師與病人討論的重點。

尤其尿失禁是根治手術較常見的併發症，約有四分之一的專家們最顧慮此一問題。不過隨者機械手臂輔助的手術發展，尿失禁的發生率已逐次下降。最終，多數專家認為對於LAPC 治療的選擇，最顧慮的依然是疾病的控制。

Long-term health-related quality of life after primary treatment for localized prostate cancer: results from the CaPSURE registry. Eur Urol. 2015 Oct;68(4):600-8.

子題2-13

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選項 3 5

所有專家 (N=46)

21%

74%

10%

83%

55%

45%

25%

75%

資深醫師 (N=25)

21%

75%

此題與上一題類似，疾病控制依舊是大部分醫師所最看重的。不過可以看到有超過一半的放射腫瘤科醫師，比較在意放射性直腸炎。

Long-term health-related quality of life after primary treatment for localized prostate cancer:

results from the CaPSURE registry. Eur Urol. 2015 Oct;68(4):600-8.

For patients with LAPC who are counseled about EBRT, which of the followings concerns you most? (單選)

【選項】

2% 1. Erectile dysfunction

3% 2. Urinary incontinence or voiding dysfunction 27% 3. Radiation proctitis

12% 4. Radiation cystitis 52% 5. Disease (cancer) control

0% 6. Secondary tumor after radiotherapy 0% 7. Gastrointestinal disorders

0% 8. None of the above

•評論分析：

•參考資料：

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58

子題2-15

絕對多數的專家不會對於攝護腺切片陰性的病人施以任何局部治療。國外雖有類似報告提供參考，但作者Andrew Keller仍建議此非常規，需與病人充分溝通。

Case Report: Radical prostatectomy without prostate biopsy in PI-RADS 5 lesions on 3T multi-parametric MRI of the prostate gland. F1000Research 2015

Do you or your hospital perform local definitive treatments for patients who have suspected prostate cancer but the prostate biopsy was negative? (請選擇一個最好的答案)

【選項】

87% 1. Never.

3% 2. Yes, sometimes when the chance of cancer is high (eg. >50%).

1% 3. Yes, sometimes when patients urge me to do it for them.

2% 4. Yes, whenever patients accept my suggestions of aggressive treatments.

3% 5. Yes, but for other reasons.

•評論分析：

•參考資料：

選項 1

所有專家 (N=46)

98%

97%

100%

資深醫師 (N=25)

100%

(23)

針對此一假定病人，全部專家仍不同意施行局部治療。

Do you or your hospital perform local definitive treatments for patients who have suspected prostate cancer but the prostate biopsy was negative? Assume a patient of 65 years, ECOG 0-1, DRE T3a, PSA 30. (請選擇一個最好的答案)

【選項】

88% 1. Never.

6% 2. Yes, sometimes when the chance of cancer is high (eg. >50%).

0% 3. Yes, sometimes when patients urge me to do it for them.

2% 4. Yes, whenever patients accept my suggestions of aggressive treatments.

0% 5. Yes, but for other reasons.

•評論分析：

選項 1

所有專家 (N=46)

100%

資深醫師 (N=25)

100%