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ECCLU 2011 - M. Bolla - Prostate cancer: Locally advanced disease and patient advocacy - Adjuvant versus salvage radiation
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ECCLU 2011 - M. Bolla - Prostate cancer: Locally advanced disease and patient advocacy - Adjuvant versus salvage radiation

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  • The combination of AD and RT represents a long story, written thanks to a lot of phase III trials and this story is still going on.
  • Before saying that radiotherapy might be mandatory in case of positive margins, we must keep in mind that there are several causes of variation as regard the status of surgical margins
  • This variation of assessment is clearly shown by the comparison of results between local and review pathologist and is depending on the number of cases managed per year by the centre as shown on this slide: the higher the number of cases, the higher the agreement with the review pathologist
  • looking at the biochemical PFS in the wait and see arm of the EORTC trial, the review pathology assessment is a much stronger predictor of outcome than the local review.
  • the anatomical site of the margin as well as the number of positive margins have a negative impact on the biochemical PFS in the wait and see arm of the EORTC trial.
  • consensus guidelines have been established by the International Society of Urological Pathology to reduce the disagreement Therefore the status of margins on the pathological report is of paramount importance In conclusion, consensus guidelines have been established to reduce the disagreement between pathologists,such as
  • according to the EUA guidelines
  • a better knowledge between surgeons and radiation oncologist culture, must help us better understand the field of our cooperation, adjuvant radiotherapy coming not to sign the end of the surgical act, but as a mean to destroy the infra clinical disease potentially left by the surgeon, has indicated by the pathological prognostic factors, with far less time than the one spent between the first human step on the earth and the firts one on the moon.
  • To enter into the debate allow me first to look at retrospective analysis and I will focus your attention on pT3 pN0 patients
  • The benefit is strongest for patients with Gleason score <8
  • As you can see, patients with salvage RT, whatever the combination with HT are going better, and patients with no salvage RT are going worse.
  • It is difficult to talk only about positive surgical margins, since in the EORTC trial +SM occur in less 16% so I will talk about patients classified pT3 whatever the surgical margin status is .
  • Here please mention that there was likely some underreporting of events, but most likely of low grade events and similarly in both arms, thus even if absolute rates might be somewhat under repported, the difference between groups is unliklly biased

Transcript

  • 1. Prostate cancer Adjuvant versus salvage radiation Bolla Michel Educational Cancer Convention Lugano May 13 2011
  • 2. Potential causes of variation in surgical positive margin status (10-40 %)
    • Variation in skills of urologist
    • Patient selection
    • Pathologist factor :
        • Complete or incomplete processing of specimen
        • Interobserver variation in assessment
  • 3. Agreement between local and review pathology according to center size
    • Simple Kappa
    • Parameter Overall All centers Centers Centers
    • agreement (%) >75 cases <50 cases
    • SV Invasion 92.8 0.83 0.83 0.79
    • ECE 68.2 0.33 0.35 0.17
    • SM Status 69.4 0.45 0.45 0.29
  • 4. Biochemical PFS in the wait-and see arm by margin status (review vs local pathologist) (years) 0 2 4 6 8 10 0 10 20 30 40 50 60 70 80 90 100 O N Number of patients at risk : Margin status 22 76 65 34 12 6 22 33 21 10 4 2 11 40 30 19 13 5 57 119 86 48 23 6 Loc - / Rev - Loc - / Rev + Loc + / Rev - Loc + / Rev + Local - / Review - Local - / Review + Local + / Review - Local + / Review + Van der Kwast TH et al. Virchows Archiv 2006; 449: 428-434.
  • 5. Van der Kwast, T. H. et al. J Clin Oncol; 25:4178-4186 2007 Biochemical progression-free survival according to margin status and localization for patients in the control arm EORTC Trial 22911
  • 6. Consensus 1 Tumour extending close to the capsular margin, but not into it, should be reported as NEGATIVE Consensus 2 Location(s) of positive margins should be reported as posterior, posterolateral, lateral, anterior at either apex, mid or base. Consensus 3 The extent of a positive margin should be reported as mm of involvement. The ISUP Consensus Conference on Handling and Staging of the Radical Prostatectomy Specimen.
  • 7. Guidelines and recommendations for radical prostatectomy and definitive radiation therapy Heindenreich A. et al Eur Urol . 2011, 59 , 61-71
  • 8. Time needs time…
  • 9. All margin positive patients after RP should have radiotherapy ?
    • Retrospective data
    • pT3 R0-1 pN0 M0 PCa
    Educational Cancer Convention Lugano May 13 2011
  • 10. Results of salvage therapy Edouard J. Trabulsi, Richard K. Valicenti, Alexandra L. Hanlon, Thomas M. Pisansky, Howard M. Sandler, Deborah A. Kuban, Charles N. Catton, Jeff M. Michalski, Michael J. Zelefsky, Patrick A. Kupelian, Daniel W. Lin, Mitchell S. Anscher, Kevin M. Slawin, Claus G. Roehrborn, Jeffrey D. Forman, Stanley L. Liauw, Larry L. Kestin, Theodore L. DeWeese, Peter T. Scardino, Andrew J. Stephenson, and Alan Pollack UROLOGY 2008;72:1998-1302 A multi-institutional and salvage postoperative radiation therapy for pT3-4 N0 prostate cancer
  • 11. Methods
    • Multi-institutional database of 2299 patients
    • 449 pT3-4N0 : 211 (Adjuvant RT) and 238 (Salvage RT).
    • 192 patients matched according to preoperative PSA, Gleason score, seminal vesicle invasion, surgical margin status, and follow-up from date of surgery.
    • Median follow-up : 94 months from surgery and 73 months from RT completion.
  • 12. 5-year biochemical progression-free survival (from date of surgery)
  • 13. 5-year biochemical progression-free survival (from end of RT)
  • 14. Cancer-specific survival following salvage radiotherapy vs observation in men with biochemical or local recurrence after radical prostatectomy (1982-2004)
    • Bruce J. Trock, PhD, Misop Han, MD, Stephen J. Freedland, MD, Elizabeth B. Humphreys, MS, Theodore L. DeWeese, MD, Alan W. Partin, MD, PhD, Patrick C. Walsh, MD
    JAMA. 2008;299:2760-2769
  • 15. Median follow-up : 6 yrs after recurrence, 9 yrs after surgery
  • 16. All margin positive patients after RP should have radiotherapy ?
    • Phase III randomized trials
    • pT3 R0-1 pN0 M0 PCa
    • EORTC 22911 (1992-2001)
    • SWOG (1988-1997)
    • ARO 96-02 (1997-2004)
    Educational Cancer Convention Lugano May 13 2011
  • 17. Safety margins for adjuvant radiotherapy 15 15 15 12
  • 18. EORTC trial 22911 DESIGN Wait and see (W&S) until local failure Post-op radiotherapy (RTX: 60 Gy/6wks) 1005 patients with pT2-T3N0 prostate cancer operated and randomized were entered from 1992 to 2001 First study results with 5 years median follow-up (Bolla et al. Lancet 2005) showed significant difference in clinical and biochemical progression-free survival The median follow-up is now 10.6 years Randomization Extraprostatic invasion and/or S eminal vesicle invasion and/or Positive surgical margins S U R G E R Y Who PS 0-1 Age  75 y T0-3N0M0 PCa
  • 19. Pathological Risk factors Combination of risk factors Wait-and-See (N=503) Irradiation (N=502) Total (N=1005) N (%) N (%) N (%) No risk factor (ineligible) 0 (0.0) 2 (0.4) 2 (0.2) ECE+ only 127 (25.2) 139 (27.7) 266 (26.5) SV+ only 19 (3.8) 23 (4.6) 42 (4.2) SM+ only 79 (15.7) 84 (16.7) 163 (16.2) ECE+ ,SV+, SM- 40 (8.0) 26 (5.2) 66 (6.6) ECE+, SV-, SM+ 169 (33.6) 149 (29.7) 318 (31.6) ECE-, SV+, SM+ 8 (1.6) 16 (3.2) 24 (2.4) ECE+, SV+, SM+ 61 (12.1) 63 (12.5) 124 (12.3)
  • 20. Late treatment complications (years) 0 2 4 6 8 10 12 14 16 18 0 10 20 30 40 50 60 70 80 90 100 O N Number of patients at risk : Treatment Arm 306 503 259 219 174 126 85 35 7 0 348 502 201 166 121 89 50 21 7 0 82 503 444 407 357 287 204 103 35 1 121 502 408 374 316 262 176 81 22 1 15 503 477 442 395 326 235 119 40 1 27 502 457 433 375 316 215 99 33 1 Gr>0 W&S Gr>0 RT Gr>1 W&S Gr>1 RT Gr>2 W&S Gr>2 RT Wait-and-See Irradiation Grade >0 @ 10 years 70.8% vs 59.7% Grade >1 23.6% vs 14.8% Grade >2 5.3% vs 2.6%
  • 21. Impact of baseline factors: bioch PFS Events / Patients Irradiation Wawa Statistics (O-E) Var. HR & CI* : (Irradiation Wait-and-See) HR (95% CI) *95% CI everywhere Treatment effect: p<0.00000 better better Irradiation Wait-and-See 0.25 0.5 1.0 2.0 4.0 Heterogeneity te st (df=2) : p=0.04 Total 198 / 502 311 / 503 -88.3 124.5 0.49 (0.41;0.59) (39.4 %) (61.8 %) >=70 51 / 94 65 / 102 -8.4 28.8 0.75 (0.52;1.08) 65-69 69 / 170 112 / 165 -34.5 44 0.46 (0.34;0.61) Age (years) <65 78 / 238 134 / 236 -43.5 51.5 0.43 (0.33;0.56) Heterogeneity test (df=3) : p>0.1 SV+ 76 / 128 93 / 128 -20.8 41 0.60 (0.44;0.82) SM+ ECE+ 50 / 149 109 / 169 -37.4 39 0.38 (0.28;0.52) SM- ECE+ 47 / 139 67 / 127 -16.9 27.8 0.54 (0.38;0.79) Local pathology SM+ ECE- 24 / 84 42 / 79 -14.2 16 0.41 (0.25;0.67) Heterogeneity test (df=1) : p>0.1 >0 2 69 / 127 103 / 133 -29.2 41.7 0.50 (0.37;0.67) Postop PSA (ng/ml) <=0 2 121 / 353 192 / 345 -55.4 76.6 0.49 (0.39;0.61)
  • 22. Biochemical PFS (intent-to-treat) (years) 0 2 4 6 8 10 12 14 16 18 0 10 20 30 40 50 60 70 80 90 100 O N Number of patients at risk : Treatment Arm 311 503 373 278 227 172 122 53 16 0 198 502 440 384 319 260 173 83 28 1 Wait-and-See Irradiation 60.6% (55.7 – 65.2) 41.1% (36.4– 45.8 ) HR=0.49 95.7%CI: (0.41,0.59) Logrank P<0.0001 Wait and see Post-op RT
  • 23. Clinical PFS (intent-to-treat) (years) 0 2 4 6 8 10 12 14 16 18 0 10 20 30 40 50 60 70 80 90 100 O N Number of patients at risk : Treatment Arm 181 503 451 397 347 275 186 89 30 0 157 502 459 424 363 308 206 102 34 1 Wait-and-See Irradiation 70.3% (65.5 – 74.6) 64.8% (59.8– 69.3) HR=0.81 95.7%CI: (0.65, 1.01) Logrank P=0.539 Wait and see Post-op RT
  • 24. Overall survival (intent-to-treat) (years) 0 2 4 6 8 10 12 14 16 18 0 10 20 30 40 50 60 70 80 90 100 O N Number of patients at risk : Treatment Arm 115 503 482 451 403 333 241 124 42 1 130 502 468 449 391 334 226 109 37 1 Wait-and-See Irradiation 80.7% (76.4 – 84.3) 76.9% (72.4– 80.8) HR=1.18 95.7%CI: (0.91, 1.53) Logrank P=0.202 Wait and see Post-op RT
  • 25. Distant control (years) 0 2 4 6 8 10 12 14 16 18 0 10 20 30 40 50 60 70 80 90 100 O N Number of patients at risk : Treatment Arm 57 503 475 432 386 314 225 114 41 1 55 502 464 434 375 319 210 105 36 1 Wait-and-See Irradiation 11.0% (8.0– 14.0) 10.1% (47.2– 13.0) HR=0.99 95.7%CI: (0.67, 1.44) Logrank P=0.938 Wait and see Post-op RT
  • 26. Deaths due to prostate cancer (years) 0 2 4 6 8 10 12 14 16 18 0 10 20 30 40 50 60 70 80 90 100 O N Number of patients at risk : Treatment Arm 34 503 482 451 403 333 241 124 42 1 25 502 468 449 391 334 226 109 37 1 Wait-and-See Irradiation 5.4% (3.2– 7.5) 3.9% (2.0– 5.7) HR=0.78 95.7%CI: (0.46, 1.33) Logrank P=0.341 Wait and see Post-op RT
  • 27.
    • Prostate bed should include:
      • Centrally: the urethra-vesical anastamosis
      • Cranially: the bladder neck
      • Posteriorly: up to but not including the outer rectal wall including the most posterior part of the bladder neck
      • Caudally: the apex
      • Laterally: the neurovascular bundles
      • Anteriorly: the anastamosis and urethral axis
    EORTC Target Volume Delineation Guidelines
  • 28. ARO Trial Biochemical progression-free survival of all patients with undetectable PSA Wiegel T.W. J Clin Oncol doi : 10.1200/JCO.2008.18.9563
  • 29. SWOG Trial Metastis-free survival Thompson I.M et al – J. Urol 2009;181:956-962 p = 0.016
  • 30. Metastis-free survival for radiotherapy arm stratified by PSA after prostatectomy p = 0.03 Thompson I.M et al – J. Urol 2009;181:956-962
  • 31. SWOG Trial Overall survival Thompson I.M et al – J. Urol 2009;181:956-962 p = 0.023
  • 32. EORTC 22043-30041 M.Bolla, H.van Poppel Post-operative 3DCRT/IMRT 64 Gy/32 fr/6.5wks cT1-2 or cT3a, N0M0 PSA  20 ng/ml WHO 0-1 Age  80 y pT2R1N0M0 Gleason 5-10 Undetectable PSA R SAME + 6 months HT (1mo AA starting 15d prior d1 of RT, one 6mo depot injection of LH-RH on d1 of RT) pT3a-bR1N0M0 Gleason 5-10 Undetectable PSA Radical Px with LN dissection or LN sampling  3 months from RPx to R  4 months from RPx to d1 of RT (but patient must be fully continent when initiating RT) pT3a-bR0N0M0 Gleason 5-10 Undetectable PSA
  • 33. Adjuvant High dose IMRT
    • 104 patients pT3a-b R0-1, or pT2 R1 after RP.
    • Median dose: 74 Gy (72-80 Gy)
    • 6-month AD : pT3b, bPSA >20 ng, Gleason > 4+3 (36)
    • or urologist personal preference (32)
    • Median follow-up : 36 months
    • 3-year and 5-year BDFS : 93 %
    • Acute grade 3 GU : 8%, late grade 3GU : 4%
    • Ost P. et al. Eur Urol 2009, 56 : 669-677
  • 34. MRC « Radicals » R adiotherapy and A ndrogen D eprivation I n C ombination A fter L ocal S urgery
  • 35. Conclusions
    • Conventional post-operative radiotherapy improves biochemical PFS and local control
    • After 10 years median follow-up, it does not impact on distant metastases nor overall survival.
    • Initiation of salvage treatment upon PSA failure and a greater proportion of deaths in that endpoint may dilute an effect.
    • Old age seems to significantly influence treatment benefit with patients >= 70 years benefiting less. Margin status is also influential.
    • The immediate RT arm of the EORTC study led to similar results as the RT arm of the SWOG trial, but the OBS arm in EORTC fared better. Worst patient prognosis in the SWOG study may explain this.
  • 36. All margin positive patients after RP should have radiotherapy
    • Adjuvant radiotherapy has to be part of the tacit contract established between the urologist and the patient, before radical prostatectomy.
    Educational Cancer Convention Lugano May 13 2011
  • 37.
    • Within the frame of therapeutic education, the patient has to know that based on the comprehensive analysis of the pathologist, the presence of poor prognostic factor(s) may indicate the opportunity of an adjuvant treatment to prevent the risk of biochemical or local relapse -which like the spectrum of a Damocles sword over his head- may alter his quality of life.
    Educational Cancer Convention Lugano May 13 2011 All margin positive patients after RP should have radiotherapy