Debate: Whole pelvic RT for high risk prostate cancer??

Transcription

1 Debate: Whole pelvic RT for high risk prostate cancer?? WPRT well, at least it ll get the job done.or will it? Andrew K. Lee, MD, MPH Associate Professor Department of Radiation Oncology Using T-stage, Gleason, PSA to define risk of failure in LOCALIZED prostate cancer Localized prostate cancer Low Risk Intermediate Risk High Risk T1c-2a Gleason 2-6 PSA 0-10 T2b or Gleason 7 or PSA T2c or Gleason 8-10 or PSA >20 1

2 Risk of what? Risk of biochemical recurrence after conventional local therapy Radical prostatectomy External beam radiation therapy Brachytherapy implant How are we classifying high risk? D Amico: T2c+ or Gleason 8-10 or PSA >20 NCCN: High: T3a or Gleason 8-10 or PSA >20 Multiple Intermediate risk factors (T2b,c + Gleason 7 + PSA 10-20) Very high: T3b or Multiple high risk factors Why not use whole pelvic RT (WPRT) for high risk patients? Nodal risk is over-estimated in modern era Value of WPRT not validated in RCT Value of WPRT not validated in modern era Value of WPRT not validated in setting of doseescalation Clinical benefit of WPRT not clear Competing risks of other failure events (LF, DM) More side effects (Severe GI: 5% vs. <2%) WPRT doubled severe (grade 3) & moderate (grade 2) GI Sx Roach et al. IJROBP 66,

3 Determining nodal risk: A disconnect between risk group and nodal involvement? Nodal risk for high risk ~7% as per CaPSURE Roach: 2/3 PSA + (GS-6) x 10 Used 1993 Partin tables Overestimates nodal risk in modern era Threshold risk of >15% typically used to recommend WPRT Kawakami et al. J Urol 176, 2006 What about SEER? Analysis of 9,387 men w/ surgical LN evaluation in 2004 Overall node (+) rate 3.3% Roach formula overestimated LN+ by: 16x for Roach risk <10% 7x for Roach risk 10-20% 2.5x for Roach risk >20% T1c, 4+4 (4/12+), PSA 12 Roach formula: N+ risk 28% Partin Tables (2007) N+ risk 9% MSKCC nomogram N+ risk 6.5% Nguyen et al. IJROBP 74,

4 Let s go back to SEER data Why is there decrease in nodal involvement? Better staging and patient selection for surgery Stage migration (PSA screening) Gleason grading migration Fewer lymph nodes removed? Also consider potential selection bias: Surgeon likely to do more extensive LND for higher risk features Is there prospective clinical rationale for WPRT in high risk patients? Most RCT showing benefit to RT+HT did use pelvic nodal fields except EORTC where 20% in each arm received small fields They also used conventional or 3DCRT and <71Gy GETUG men w/ T1b-3, N0 randomized to pelvic (46Gy) vs. prostate only RT (66-70). High risk patients (79%, T3, GS 7 or PSA>12) allowed 4-8 mos HT About 50% of patients had Roach risk >15% RTOG 9413 GETUG-01 Negative Negative 58-60% received HT (neoadjuvant + concurrent) No difference in 5y PFS Pommier et al. J Clin Oncol 25,

5 High risk GETUG 5-yr PFS Low risk RTOG men (Roach risk >15% or T2c-4) randomized 2x2 factorial WPRT (50.4) vs. PORT (70.2) Neoadjuvant (NHT) vs. Adjuvant HT (AHT) x 4mos. Median FU 6.7 yrs (7 yrs for alive) (RTOG suggests median FU 2y longer than endpoint reported) *Only 8% of pts had clinical progression (local, nodal, and/or DM), despite 50% having Roach risk >15% *Relatively small 4 years for both risk groups No difference PFS in NHT vs. AHT No difference PFS in WPRT vs. AHT? Difference if WPRT + NHT? Roach et al. JCO 21, Updated Lawton et al. IJROBP 69, PFS WPRT vs. PORT Bonferroni correction Multiple-comparison correction used when comparing several dependent or independent hypotheses on a set of data Significance would be α/n (where n=number of comparisons) p-value 0.05/3 =

6 PFS for all 4 groups Overall survival WP+NHT vs. PO+AHT, p=0.75 WP+NHT PO+AHT Cancer-specific survival Non-PCa survival No comment needed Both WP arms eventually do worse than PORT 6

7 RTOG 9413 No difference in WPRT vs. PORT although WPRT+AHT resulted in greatest number of failures and ultimately, deaths. WHY? LF and DF outpaces NF about 6x Even if one assumes statistical significance, clinical significance is questionable. Giving PORT+AHT as good as WPRT+NHT Roach et al. JCO 21, CT report:..i do not see any retrocrural, retroperitoneal, pelvic, or inguinal lymphadenopathy. There is no evidence of mesenteric lymphadenopathy. In a RCT, nodal failure rates were low after high dose local radiation Kuban et al. IJROBP 79,

8 Pelvic RT does not benefit men receiving high doses to prostate & SV 1432 men treated between treated w/ EBRT and HDR Roach risk >15% in men P&SV matched w/ 250 men WPRT Median FU 4 years No difference in bned, DM, EFS, CSS, OS Kuban et al. IJROBP 79, 2011 Vargas et al. Am J Clin Oncol 29, 2006 Freedom from DM WPRT did not improve 4y outcomes among subset receiving neoadjuvant HT (median 4 mo) CSS Vargas et al. Am J Clin Oncol 29, 2006 Vargas et al. Am J Clin Oncol 29,

9 Just because it s a nice story does not make it true This analysis restricted to NHT subset: Where s PORT+AHT? D Amico randomized RT vs. RT+HT for localized (T1-2) intermediate and high risk Randomized study 206 mostly intermediate and some high risk prostate cancer patients T1-2b, Gleason 7, PSA , MRI T3 RT (70.35 Gy) vs. RT + HT (TAB 6 mo) Median FU 7.6 years Significant benefit to HT 5-y salvage-free survival 82 vs 57% 8-y overall survival 74 vs 61% Benefit primarily in men w/ low comorbidities Roach et al. IJROBP 66, 2006 D Amico et al. JAMA 292, 2004 JAMA 299,

10 Salvage-free (progression-free) survival 8-y overall survival: 74% vs. 61% Post-hoc analysis int & high risk In men w/ no to minimal comorbidity 7y OS for high risk 89% vs. 51.2% (p=0.007) 7y OS for int risk 91% vs. 86% (p=0.009) Risk of death Adjusted HR 3.0 [CI, ], p=0.01 Nguyen et al. IJROBP

11 Doctor, should we target the nodes or the prostate? Sagittal dose distribution The longer you wait the more 2 nd cancers you get 10-14y RR 1.6, >15y RR 1.91 de Gonzalez et al. Lancet Oncol, Mar

12 Doses >5Gy associated w/ increased risk of 2 nd cancers de Gonzalez et al. Lancet Oncol, Mar