The document discusses radiation treatment of pelvic lymph nodes in prostate cancer. It summarizes several key studies that have evaluated treating lymph nodes in patients with suspected lymph node involvement (cNx) or positive lymph nodes (pN+). Treating lymph nodes reduced the risk of recurrence compared to prostate-only radiation. However, whole pelvic radiation was associated with increased side effects. Newer intensity modulated radiation therapy (IMRT) techniques can reduce toxicity while adequately treating lymph node regions. An upcoming study called ART-2 aims to evaluate the benefit of radiation treatment of pelvic lymph nodes for pN+ patients after prostatectomy.

1. Managing pelvic lymph nodes and related toxicity - Radiation perspective - Thomas Wiegel

2. Points of Discussion RT of suspected disease (cNx) RT of positive node PCA (pN+) When to treat, how to treat pelvic nodes? Side effects Upcomig ARO-study for pN+ patients after RP

3. RT of suspected disease (cNx)

4. Risk of LN(+) for cN0 PCA - „High Risk“ (>15%) - Roach III, Int. J. Radiat. Oncol. Biol. Phys. 28, 1993 LN(+)=(2/3) PSA+[(GS-6)  10] PSA: 30 Gleason score:8 = est. risk 40% • Risk overestimated, only 212 Pat. investigated Standard RTOG (formerly)

5. RTOG 9413 Roach III M et al., J Clin Oncol 10, 2003 04/1995 and 6/1996, 1.323 patients localized PCA with PSA  100 ng/mL and estimated risk of LN(+) >15%* Whole-pelvic (WP) RT + neoadjuvant and concurrent HT (NCHT) Prostate-only (PO) RT + NCHT WP + adjuvant hormonal therapy (AHT) PO + AHT Med. follow-up: 60 months Primary endpoint: PFS after 5 years * LN(+)=(2/3) PSA+[(GS-6)  10]

6. RTOG 9413 Roach III M et al., J Clin Oncol 10, 2003

7. RTOG 9413 Roach III M et al., J Clin Oncol 10, 2003

8. RTOG 9413 Roach III M et al., J Clin Oncol 10, 2003

9. RTOG 9413 - Update Lawton CA et al., Int J Radiat Oncol Biol Phys 69, 2007

10. RTOG 9413 – Update - med. FU 6.6 years Lawton CA et al., Int J Radiat Oncol Biol Phys 69, 2007

11. RTOG 9413 - Update Lawton CA et al., Int J Radiat Oncol Biol Phys 69, 2007

12. RTOG 9413 - Update Lawton CA et al., Int J Radiat Oncol Biol Phys 69, 2007

13. RTOG 9413 - Update Lawton CA et al., Int J Radiat Oncol Biol Phys 69, 2007 bNED protocol definition Phoenix definition

14. RTOG 9413 - Update Lawton CA et al., Int J Radiat Oncol Biol Phys 69, 2007

15. GETUG-01 Pommier P et al., J Clin Oncol 25, 2007 12/1998 and 6/2004, 444 patients, T1b-T3, cN0 M0 Low risk LN+: T1-2, Gleason <7, PSA < 3x upper local limit High risk: T3, Gleason >6 and/or PSA > 3x upper local limit pelvic and prostate RT or prostate RT only stratified according LN involvement Short-term 6-month neoadjuvant and concomitant HT allowed only high-risk group Pelvic dose 46 Gy, Total dose prostate: 66 – 70 Gy Med. follow-up: 42 months

16. GETUG-01: Progression-free survival Pommier P et al., J Clin Oncol 25, 2007 High-risk group Low-risk group 5-year PFS and overall survival similar in the two treatment arms

17. Roach et al., Br. J. Cancer 2005 All major elderly Phase-III-studies with RT pel. LN

18. RT of positive node PCA (pN+)

19. MD-Anderson-trial (retrospective) Zagars et al., Urology 58, 2001 255 men, LN (+), no RP, staging LADN N=183, androgen ablation alone N=72, plus RT (discretion of the urologist) )

20. MD-Anderson-trial (retrospective) Zagars et al., Urology 58, 2001 Clear advantage for RT + AA OS PFS

21. Lawton et al., J. Clin. Oncol. 23, 2005 AA + RT versus RT (RTOG 85-31) Retrospective subgroup-analysis

22. Lawton et al., J. Clin. Oncol. 23, 2005 AA + RT versus RT alone (RTOG-trial 85-31) OS

23. Lawton et al., J. Clin. Oncol. 23, 2005 No data from a prospective trial are available. „ So until such data are available, RT and immediate hormonal manipulation clearly remain an effective means to control pN+ PCA in a significant cohort of men with such aggresive disease...“

24. Da. Pozzo et al., Eur. Urol. 55, 2009 Adjuvant RT for LN (+) – pts. after RP Retrospective series N=250 Patients

25. Da. Pozzo et al., Eur. Urol. 55, 2009 Adjuvant RT for LN (+) – pts. after RP

26. Briganti et al., Eur. Urol. 2011, in press Adjuvant RT for LN (+) – pts. after RP Retrospective matched pair analysis Milan and Rochester N=703 pts. 1986-2002 All RP, stage pT2-4 pN1 Group I: 117/171 pts. ART+HT Group II: 247/532 pts. HT Median FU: 95 months Lack of standardised HT and RT

27. Briganti et al., Eur. Urol. 2011, in press OS in the overall matched population 84% vs. 65% 19% better OS

28. Briganti et al., Eur. Urol. 2011, in press OS for pts. with <= two LN 19% better OS

29. When to treat, how to treat pelvic lymph nodes? Target volume Technique

30. Lawton et al., Int. J. Radiat. Oncol. Biol. Phys.74, 2009 14 RTOG GU-Radiation-Oncologists Contoured the iliac and presacral lymph nodes 2 men available for treatment planning

31. Lawton et al., Int. J. Radiat. Oncol. Biol. Phys.74, 2009 Results: Minimum,maximum. mean iliac volumes: 82, 877 and 338 ml Overall agreement „moderate“ (kappa=0.53 and kappa 0.48) 0.61-0.8 „substantial“ agreement No volume of 100% agreement for either two presacral volumes

32. Lawton et al., Int. J. Radiat. Oncol. Biol. Phys.74, 2009 Conclusion: Consus urgently needed

33. Periprostatic LN www-rtog.org RTOG consensus for delineation of the target volume

34. Iliac lymph nodes www-rtog.org/ Lawton CA, Int. J. Radiat. Oncol. Biol. Phys. 74, 2009

35. Presacral nodes RT Pelvic Lymphatics (CTV) www-rtog.org

36. IMRT of the pelvic lymphatics - Comparison 3D-planning vs. IMRT - 3-D-RT IMRT

37. Dose wash 3-D-Planning IMRT 5 Fields 6 Fields

38. „ Fast“ IMRT – Rapid Arc/Volumetric Arc Technique/Tomo Yoo et al., Int J Radiat Oncol Biol Phys 76 (2010) Bladder- and rectum sparing

39. Ashman et al., Int. J. Radiat. Oncol. Biol. Phys.63, 2005 Wang-Chesebro et al., Int. J. Radiat. Oncol. Biol. Phys. 66, 2006 Ganswind et al, Int J. Radiat. Oncol. Biol. Phys. 67, 2007 IMRT of the pelvic lymphatics Reduction of dose and volume to small bowel Mean dose: 33 Gy vs. 26 Gy

40. Side effects

41. RTOG 9413 Roach III M et al., J Clin Oncol 10, 2003 • Neoadj. TAB 2 mo. before/during RT pel. LN + Boost • Neoadj. TAB 2 Mo. before/during RT of prostate • RT pel. LN + prostate + 4 mo. adjuvant HT • RT prostate + 4 mo. adjuvant HT

42. GETUG-01: Acute and late Toxicity Pommier P et al., J Clin Oncol 25, 2007

43. Chung et al., Int. J. Radiat. Oncol. Biol. Phys. 71, 2009 Comparison IMRT vs. IMRT/IGRT RT pelvic lymphatics Significant reduced acute Side effects II (p=0.004) Small prospective series – 10 vs. 15 Pts.

44. Upcoming ARO-study for pN+ after RP (ART-2)

46. ART-2-Study bNED after 5 years for pN+ Bern study – none HT 1 LN+: 24.7% bNED >= 2 LN+: 11.8% 4.9% Schuhmacher et al., Eur. Uro. 54, 2008

47. ART-2-Study Augsburg (unpublished) - pN+ bNED after 3 years – none HT micro metastases (0.2 – 2mm)(20/56): 64% metastases (55/74): 35% 1micro metastasis: undetectable range: 86% 1 metastasis: undetectable range: 56% >1 metastasis: 47% Weckermann et al., Augsburg

48. Flow-Chart ART-2 study No hormonal treatment! RP (</= 2 LK-mets) Central pathologic review PSA Undetectable range (<0.1 ng/ml) R Wait and See RT pelvic lymphatics (50.4 Gy) SM +: 64.8 Gy SM: + or -

49. ART-2-study Endpoint and statistics bNED after 4 years: 40% and 55% Power 80%, alpha-error 5% Drop-out 10% Per arm 103 patients Total: 206 patients 20 centers 2-3 pts/year central path. review before R

50. ART-2-study Radiotherapy RT pel. LN: IMRT/IGRT SD 1.8 Gy TD 50.4 Gy Prostate bed: 50.4 Gy R1: 64.8 Gy Target volume: RTOG

51. ART-2-study Stratification Gleason-score <7 vs. >=7 Margin R1 vs. R0 Stage: pT2 vs. >pT2 PSA before R.: <0.03 vs. >0.03<0.1 Metastases: Micromets. vs. 1 Mets. vs. 2 Mets

52. Conclusions cNx: to belive or not to belive pN+: Studies needed Technique: low side effects with IMRT/IGRT

53. Urologists and Radiation Oncologists are friends!