Important Studies Flashcards
Adjuvant Long Term ADT vs. Short Term ADT
DART01/05 GICOR: “Zapatero et al, Lancet Oncol, 2015. 53% high risk, 47% int risk. “→28 mos ADT + 76-82 Gy RT (includes 4 mos ADT neoadjuvant)
vs. 4 mos NCADT + 76-82 Gy RT. There is benefit in OS and DM when adding LT-ADT to high risk patients with dose escalated RT. Dose escalation does not negate the benefit of ADT.
RTOG 9202. “Hanks et al, JCO, 2003. Modern high risk, some intermediate. “→4 mos NCADT + 65-70 Gy RT (with 44-50 Gy WPRT) alone vs. with 24 mos adj ADT (28 mos total). LT ADT improves LR, DM, BF, and CSS. OS is improved in GS 8-10. Most of these patients were high risk.
Adjuvant Long Term ADT vs. int length ADT
PSC IV: Nabid et al, Eur Urol, 2018. “High risk: T3-4, PSA>20, or GS>7. →ADT 18 mos vs. ADT 36 mos. RT to 70 Gy with WPRT 44 Gy (4.5 Gy per week hypofractionation). 36 months of ADT is not superior to 18 months in high risk prostate cancer.
Whole Pelvis Irradiation
RTOG 9413: Roach et al, JCO, 2003. 2x2 randomization. Neoadj conc ADT vs. adj ADT. Prostate only RT vs. WPRT. This trial can be used to support starting ADT at any time with RT. It should be emphasized that no DM benefit was ever found at any point in any arm. This study was not powered to find differences between 4 arms. The study is criticized for its post-hoc subanalyses and statistical approach toward them. The p values were not adjusted for multiple comparisons. It seems illogical that if a 2x2 comparison was nonsignificant, then a full 4 arm comparison could then somehow be significant. Be careful of bias - it can be tempting to accept an unpowered or unplanned subanalysis when it is beneficial to you, and dismiss it when it is not.
GETUG-01: Pommier et al, JCO, 2007. “66-70 Gy to prostate vs. with WPRT to 46 Gy. RT did not improve 5-yr PFS (65-66%) or OS.
No difference when stratified by risk group, and no difference in acute and late GI toxicity or QOL
Ongoing Whole Pelvis
RTOG 0924. “Risk of LN involvement >15% based on Roach; intermediate or high risk prostate cancer “→prostate and SV RT, boost to prostate and proximal SV vs. WPRT, boost to prostate and SV
- Dose: 45 Gy in 25 fx plus either 34.2 Gy EBRT or brachy boost
- ADT: choice of 6 or 32 mos”
This trial is similar to RTOG 9413. Goal is to perform a similar trial with higher power.
ADT Benefit to RT
Regena Elena NCI, Rome, Italy. Meta-analysis of 7 trials. ADT added to RT improved BC and OS in locally advanced prostate cancer, including node positive.
RT benefit to ADT
NCIC/MRC: Warde et al, Lancet, 2012. “Leuprorelin indefinitely + flutamide 2 weeks with 65-69 Gy to pelvis, prostate, and SV vs. ADT alone. RT added to ADT improves OS in high risk and very high risk prostate cancer.
SPCG-7/SFUO-3: Widmark et al, Lancet, 2009. Leuprorelin for 3 months then flutamide indefinitely with 70 Gy RT vs. ADT alone. RT added to ADT improves OS and CSS in high risk prostate cancer.
Benefit of Short term ADT to EBRT in nonescalated dose
RTOG 8610: Pilepich et al, IJROBP, 2001. “Bulky” T2-4 tumors or tumor 5x5 cm, N+ allowed. →65-70 Gy RT alone vs. RT with 4 mos ADT (2 mos neoadj). ST ADT added to RT improves DSM, DM, DFS, and BF in locally advanced prostate cancer. Suggested that 4 months was insufficient for high risk patients
RTOG 9408: T1b-T2b; PSA≤20. Low/Int/High: 35%/54%/11%. EBRT: 66.6 Gy (prostate + nodes)
+/- 4 months neo/conc Goserelin. Subgroup analysis showed significant OS benefit only in int/high risk pts, no benefit low risk
RTOG 9910 [Pisansky JCO ‘14]: Mostly IR. 70.2 Gy + 4 vs. 9 mo nADT (2m nADT).
TROG 96.01 [Denham Lanc Onc ‘11]: 66 Gy ± 3 vs. 6 mo nADT.
EORTC 22863: “Bolla et al, NEJM, 1997. “GS 8-10 or T3-4, N0-1. Modern high risk and node positive. →RT 70 Gy (50 WPRT + 20 Gy boost) concurrent & adj ADT x 36 mos vs. RT alone. 10 yr OS 58% vs 40% .LT ADT added to RT improves OS in high risk and node positive prostate cancer.
Harvard/DFCI Trial [D’Amico JAMA ‘08, ‘15]→70 Gy to prostate and SV, 3DCRT vs. 70 Gy + ADT for 6 months (2 months neoadj). ST ADT improves OS. Most of these patients were intermediate risk.
Showed 4 month ADT insufficent in high risk?
RTOG 8610
Showed no ADT benefit for low risk?
RTOG 9408
Showed short ADT benefit for intermediate risk?
RTOG 9408, Dana Farber 95-096 (D’Amico)
Benefit of ADT to EBRT in dose escalated?
EORTC 22991: Bolla et al, NEJM, 2009. Modern high risk, node positive, and some int risk. →Noninferiority: 6 mos ADT with RT to 70 Gy (50 Gy WPRT + 20 Gy boost) then +30 months ADT (36 mos total) vs. no further ADT. OS is suprerior with 36 months of ADT compared to 6 months ADT added to RT in locally advanced prostate cancer. Most of these patients were high risk.
GETUG 14: All int risk. EBRT: 80 Gy (prostate and SVs)
+/- 4 mos neo/conc Triptorelin + Flutamide. Improved cDFS and bDFS at 5 yrs. 5 yrbcDFS 84%vs 76% (SS). No difference in OS at 5 yrs
Nabid (GU ASCO 2015): All int risk. EBRT: 70Gy or 76 Gy (prostate) +/- 6mos neo/conc Goserelin + Bicalutamide. At 10 yrs, 76 Gy + ADT still significantly betterDFS than 76 Gy alone. No difference in OS at 5 yrs
Investigating addition of short course ADT to dose-escalated EBRT for intermediate risk pts
RTOG 0815
Long term ADT+ EBRT in non-dose escalated?
RTOG 8531 [Pilepich IJROBP ‘05, Lawton JCO ‘05]: 65-70 Gy + delayed vs. immediate indefinite goserelin.
There is around 10% OS advantage with indefinite ADT in high risk patients. This becomes more pronounced in N+ group.
EORTC 22863 [Bolla Lancet Onc ‘02, ‘10]: 70 Gy ± 36 mo ADT. There is around a 20% OS advantage with 3y of ADT without evidence of late CV toxicity.
The two EORTC/Bolla trials were the first to look at 3y ADT, while Nabid asked the most relevant question (18 mo vs. 3y)
EORTC 22961 [Bolla NEJM ‘09]: Noninferiority. 70 Gy + 6 vs. 36 mo nADT. There is around 5% OS advantage with 36 mo ADT over 6 mo ADT for high risk disease.
The two EORTC/Bolla trials were the first to look at 3y ADT, while Nabid asked the most relevant question (18 mo vs. 3y)
RTOG 9202 [Horwitz JCO ‘07, ‘17] 65-70 Gy + 4 vs. 28 mo nADT. There is a greater than 10% 10y OS advantage with 28 mo ADT over 4 mo ADT for HR disease, although the OS was improved only in a post-hoc analysis of GS 8-10 subgroup. There appears to be no DFS benefit with 28 mo over 4 mo of ADT for IR disease in the dose-escalated era [DART/GICOR].
PCS IV Canadian [Nabid IJROBP ‘16, ‘18]: 70 Gy + 18 vs. 36 mo ADT. 18 mo ADT may be acceptable for HR, better QoL. Testosterone recovery may take twice as long after 3y of ADT. The lack of separation of OS from 5y to 10y suggests a potential deleterious effect of prolonged ADT.
This was not powered as a non-inferiority study, it was set as a superiority trial. Therefore, 18 mo is not standard.
Median age 71y, caution applying to younger patients. But… What about 24 months of ADT?
TROG RADAR [Denham Lanc Onc ‘19, Joseph IJROBP ‘20]: 2x2. (66-70-74 Gy or 46/23 + 19.5/3 BT) + 6 vs 18 mo ADT. TBL QS: Intermediate duration ADT for 18 versus 6 months resulted in superior prostate cancer specific mortality among a group of men with mostly high-risk prostate cancer. TBL QS: The distant progression benefit of longer ADT was independent of radiation dose in the TROG RADAR trial, and patients who received non-randomized HDR boost achieved better clinical outcomes.
Long term ADT+ EBRT in dose escalated?
There is a potential DMFS benefit with 4-6 mo ADT in unfavorable intermediate risk patients. Awaiting [RTOG 08-15] to investigate potential for increased cardiac complications with this duration of ADT in men at baseline higher cardiac risk (e.g. ACE-27).
There is an OS benefit with 18-24 mo in ADT in HR patients. This duration may be cut down to 12 mo in the setting of EBRT/BT.
GETUG 14 [Dubray ASCO ‘16]: 80 Gy ± 4 mo ADT (2mo neo/2mo concurrent).
There is a 50% RRR in DFS with 4 mo of ADT in IR disease.
EORTC 22991 [Bolla JCO ‘16]: 78 / 74 / 70 Gy ± 6 mo ADT.
ST-ADT adds a DFS benefit, with no difference by RT dose level. OS data is not yet mature.
RTOG 0815 [Protocol]: 79.2 Gy or EBRT ± brachy ± 6 mo ADT. RTOG 08-15 is stratifying according to ACE-27 comorbidity status!
DART 01/05 GICOR [Zapatero Lancet ‘15, IJROBP ‘16]: 78 Gy + 4 vs. 28 mo ADT. There is a 15% OS benefit with 28 mo over 4 mo of ADT for HR patients. There was a trend to bcF benefit in IR. There appears to be no DFS benefit with 28 mo over 4 mo of ADT for IR disease in the 70 Gy era [RTOG 9202].
Node positive benefit of ADT
RTOG 8531. Lawton et al, JCO, 2005. RT (with ADT at time of relapse) vs. RT with goserelin indefinitely. Adding hormones improved OS, bPFS, DFS, and DM. 9-yr OS 38% vs. 62%. 9-yr bPFS 4% vs. 33%. DM 33% vs. 48%. Adding ADT to RT improves BC, OS, and DM in node positive prostate cancer.
ECOG. “Messing et al, NEJM, 1999. Indefinite goserelin/orchiectomy vs. obs, with ADT to be given if symptomatic recurrence or DM. “ADT Improved OS, DSS, PFS, and BF. Median OS 13.9 yrs vs. 11.3 yrs. Early adjuvant ADT improves OS and BC over observation with salvage ADT for clinical progression (not PSA progression) for node positive prostate cancer after surgery.
