Radiation Oncology/Prostate/Hormones/Primary ADT

Primary Androgen Deprivation Therapy

Primary ADT Outcomes

 * SEER data; 2008 (1992-2002) PMID 18612114 -- "Survival following primary androgen deprivation therapy among men with localized prostate cancer." (Lu-Yao GL, JAMA. 2008 Jul 9;300(2):173-81.)
 * Cohort study. 19,271 men, age >=66, clinical T1-T2 prostate cancer, no definitive local therapy. Comparison of primary androgen deprivation (PADT) vs. conservative management. PADT in 41%
 * Outcome: 10-year CSS PADT 80% vs. conservative management 83% (HR 1.17, SS); 10-year OS 30% vs. 30% (NS).
 * Subset GS8-10: 10-year CSS PADT 60% vs. conservative management 54% (HR 0.84, SS); 10-year OS 17% vs. 15% (NS)
 * Conclusion: Primary androgen deprivation does not improve survival in cT1-T2 patients, and worsens cancer-specific survival. For Gleason 8-10, it improves cancer specific survival, but still has no impact on overall survival

Primary ADT vs. Deferred ADT

 * See also: Advanced disease#Immediate vs delayed hormonal therapy for locally advanced or metastatic prostate cancer


 * EORTC 30891 (1990-1999) -- Immediate ADT vs. Deferred ADT
 * Randomized. 985 with clinical T0-4 N0-2 M0, refused or were not suitable for local definitive treatment. Excluded if > 80 years, pain from prostate, ureteric obstruction. Arm 1) Immediate androgen deprivation vs. Arm 2) Deferred androgen deprivation at symptomatic progression.
 * 8-years; 2006 PMID 16622261 -- "Immediate or deferred androgen deprivation for patients with prostate cancer not suitable for local treatment with curative intent: European Organisation for Research and Treatment of Cancer (EORTC) Trial 30891." (Studer UE, J Clin Oncol. 2006 Apr 20;24(12):1868-76.) Median F/U 7.8 years
 * Outcome: Median OS immediate ADT 7.4 years vs deferred ADT 6.5 years (HR 1.25, SS). Most deaths due to prostate cancer (36%) or cardiovascular disease (34%). No difference in prostate cancer-specific deaths. Median time-to-start deferred ADT 7 years; 44% of patients who died never needed ADT
 * Conclusion: Immediate ADT provides modest but statistically significant increase in overall survival, but no difference prostate cancer survival
 * Timing of ADT; 2008 PMID 18191322 -- "Using PSA to guide timing of androgen deprivation in patients with T0-4 N0-2 M0 prostate cancer not suitable for local curative treatment (EORTC 30891)." (Studer UE, Eur Urol. 2008 May;53(5):941-9. Epub 2007 Dec 27.)
 * Evaluation of PSA kinetics (PSA at baseline, PSA-DT, time to PSA relapse (>2 ng/ml))
 * Conclusion: Baseline PSA >50 ng/ml or PSA-DT <12 months increased risk for PCA death, and might benefit from immediate ADT. Other patients more likely to die of non-PCA causes, and could be spared ADT
 * See also: SAKK 08/88 (Swiss multi-center) - PMID 15483020 -- "Immediate versus deferred hormonal treatment for patients with prostate cancer who are not suitable for curative local treatment: results of the randomized trial SAKK 08/88." (Studer, J Clin Oncol. 2004 Oct 15;22(20):4109-18.) Similar trial design.

Reviews:
 * 2007 PMID 17395971 Full text -- "Early versus delayed endocrine therapy for prostate cancer." (Schroder FH, Endocr Relat Cancer. 2007 Mar;14(1):1-11.)

Randomized

 * SPCG-7/SFUO-3 (1996-2002) -- ADT vs ADT + RT
 * Randomized. 875 with locally advanced prostate cancer T1b-T2 G2-G3 or T3 (78%) and PSA <70 and N0 (if PSA >11, then PLND). Arm 1) ADT (total androgen blockade x3 months, then continuous flutamide 250 mg) vs. Arm 2) Same ADT + RT 70 Gy to prostate/SV. Breast RT in 80% to prevent gynecomastia
 * Outcome; 2008 PMID 19091394 -- "Endocrine treatment, with or without radiotherapy, in locally advanced prostate cancer (SPCG-7/SFUO-3): an open randomised phase III trial." (Widmark A, Lancet. 2009 Jan 24;373(9660):301-8. [Epub ahead of print]). Median F/U 7.6 years
 * Outcome: 10-year CSS ADT 76% vs. ADT + RT 88% (SS); 10-year OS 61% vs. 70% (SS); 10-year bPFS 25% vs. 74% (SS)
 * Toxicity: Urethral stricture ADT 0% vs. ADT + RT 2% (SS), urgency 8% vs 14% (SS), urinary incontinence 3% vs. 7% (SS), erectile dysfunction 81% vs. 89% (SS)
 * Conclusion: In patients with high risk or locally advance PCA, addition of RT to ADT improved survival, with acceptable side effects
 * QoL; 2009 PMID 19286422 -- "Quality of life in patients with locally advanced prostate cancer given endocrine treatment with or without radiotherapy: 4-year follow-up of SPCG-7/SFUO-3, an open-label, randomised, phase III trial." (Fransson P, Lancet Oncol. 2009 Apr;10(4):370-80. Epub 2009 Mar 13.)
 * QoL information from 872 (99%) patients
 * Outcome: 4-year urinary moderate/severe bother ADT 12% vs ADT + RT 18% (SS), dysuria 2% vs. 4% (SS); bowel bother 7% vs. 11% (SS); erectile dysfunction 72% vs. 85% (SS). QoL similar
 * Conclusion: RT significantly increased some toxicity, but none serious. Given the substantial outcome benefit, increase in symptoms acceptable and has little effect on QoL


 * Intergroup T94-0110 (NCIC PR.3, MRC PR07, SWOG JPR3) (1995-2005) -- ADT vs ADT + RT
 * Randomized. 1205 patients, locally advanced (T3/T4, n=1057) or high risk localized (T2 and PSA >40, n=119; T2 and PSA >20 and GS >=8, n=25) N0Nx. Arm 1) lifelong ADT (bilateral orchiectomy or LHRH agonist) vs. Arm 2) lifelong ADT and RT 65-69 Gy. RT given to prostate +/- SV +/- pelvic RT.
 * 2010 ASCO Abstract -- "Intergroup randomized phase III study of androgen deprivation therapy (ADT) plus radiation therapy (RT) in locally advanced prostate cancer (CaP)" (Warde PR, J Clin Oncol 28:7s, 2010 (suppl; abstr CRA4504)) Median F/U 6.0 years
 * Outcome: 6-year death rate ADT 29% vs ADT + RT 24% (HR 0.8, SS); 10-year cancer-specific death rate ADT 23% vs ADT + RT 15% (HR 0.57, SS)
 * Toxicity: Grade 2+ GI toxicity ADT 1.3% vs ADT + RT 1.8% (NS)
 * Conclusion: Substantial overall and disease-specific survival for addition of radiation therapy to androgen deprivation
 * 2011 PMID 22056152 -- "Combined androgen deprivation therapy and radiation therapy for locally advanced prostate cancer: a randomised, phase 3 trial." (Warde P, Lancet. 2011 Dec 17;378(9809):2104-11.)
 * 7-yr OS 66% ADT vs 74% ADT + RT (HR 0.77, SS). Increased late GI toxicity.
 * Conclusion: "The benefits of combined modality treatment--ADT and RT--should be discussed with all patients with locally advanced prostate cancer."
 * 2015; Final Report PMID 25691677 -- "Final Report of the Intergroup Randomized Study of Combined Androgen-Deprivation Therapy Plus Radiotherapy Versus Androgen-Deprivation Therapy Alone in Locally Advanced Prostate Cancer." (Mason MD, J Clin Oncol. 2015 Jul 1;33(19):2143-50. doi: 10.1200/JCO.2014.57.7510. Epub 2015 Feb 17.). Median F/U 8 years
 * Outcome: 10-year OS ADT 49% vs ADT+RT 55% (SS); bPFS 46% vs 74% (SS)
 * Grade 3+ Toxicity: impotence/libido ADT 29% vs ADT+RT 33% (NS); hot flashes 8% vs 5% (NS); urinary frequency 4% vs 7% (NS); ischemia 3% vs 5% (NS). No evidence of difference in caradiovascular toxicity
 * Conclusion; Overall survival benefit maintained at 8 year median follow up
 * 2015; Long Term QOL PMID 26014295 -- "Impact of Radiotherapy When Added to Androgen-Deprivation Therapy for Locally Advanced Prostate Cancer: Long-Term Quality-of-Life Outcomes From the NCIC CTG PR3/MRC PR07 Randomized Trial." (Brundage M, J Clin Oncol. 2015 Jul 1;33(19):2151-7. doi: 10.1200/JCO.2014.57.8724. Epub 2015 May 26.)
 * Questionnaires at 6 months, 1 year, 3 years
 * Toxicity: 6-months: RT significant impact on bowel symptoms, diarrhea, urinary function, erectile dysfunction. No difference in toxicity by 3-year end point; both arms showed significant deterioration
 * Conclusion: Addition of RT to ADT had only modest and transient negative impact on quality of life


 * MRC (1980-1985) -- orchiectomy vs RT vs orchiectomy + RT
 * Randomized, 3 arms. 277 patients, clinically localized prostate cancer (T2-T4NxM0). Arm 1) RT alone vs Arm 2) orchiectomy alone vs Arm 3) RT + orchiectomy
 * 1992 PMID 1422689 -- "Treatment of advanced localised prostatic cancer by orchiectomy, radiotherapy, or combined treatment. A Medical Research Council Study. Urological Cancer Working Party--Subgroup on Prostatic Cancer." (Fellows GJ, Br J Urol. 1992 Sep;70(3):304-9.)
 * Outcome: Orchiectomy (orchiectomy alone or orchiectomy + RT) superior to RT alone in DMFS. No difference in local control or overall survival
 * Conclusion: Orchiectomy superior to RT alone in metastatic-free survival

Retrospective

 * M.D. Anderson; 2001 (1984-1998) - PMID 11489709 &mdash; "Addition of radiation therapy to androgen ablation improves outcome for subclinically node-positive prostate cancer." Zagars GK et al. Urology. 2001 Aug;58(2):233-9.
 * Retrospective. Node positive. 225 pts. Treated with androgen ablation alone or combination of RT and androgen ablation. All pts had nodal disease detected by staging pelvic lymphadenectomy, but no nodal mets detected clinically or by CT. Androgen ablation was for an indefinite time. RT begun within 3 months of lymphadenectomy. RT was four-field box to prostate + periprostatic tissues (not including wide field pelvic nodes) to 46 Gy followed by a boost to 60-78 Gy.
 * Median f/u 8.2 yrs. OS at 5,10, and 13 years was 83%, 46%, and 21% for hormone alone group. OS was 92% and 67% at 5 and 10 years for combined modality group, which was not S.S. different from an age-matched cohort without prostate cancer. NED rate was 91% and 80% at 5 and 10 yrs (RT group) vs 41% and 25%.

Primary ADT vs Primary RT

 * Uro-Oncology Study Group -- pelvic RT vs delayed ADT
 * Randomized. 73 patients, prostate limited to pelvis without evidence of node or bone extension. Arm 1) Pelvic RT vs. Arm 2) delayed hormonal therapy
 * 1984 PMID 6423840 -- "Radiation therapy versus delayed androgen deprivation for stage C carcinoma of the prostate." (Paulson DF, J Urol. 1984 May;131(5):901-2.)
 * Outcome: Failure RT 32% vs. ADT 33% (NS)
 * Conclusion: No difference in outcome