Combining Androgen Deprivation Therapy (ADT) and Salvage Radiation Therapy (SRT) improves outcomes

For the first time, a randomized clinical trial  (GETUG-AFU 16) proves that adding a short course of ADT to SRT improves the progression-free survival over SRT alone. This confirms the implications of several earlier studies, and is not especially surprising. Many radiation oncologists already integrate ADT into their SRT treatments of selected patients.

Carrie et al. (updated 5/2019) conducted a multi-institutional study in France on 743 patients with the following characteristics:

• ·      Randomized for SRT between 2006 and 2010
• ·      All had undetectable PSA post-prostatectomy
• ·      PSA≥0.2 ng/ml and <2 ng/ml at study entry
• ·      Stage pT2 (54%) or pT3 (46%)
• ·      Positive margins (51%)
• ·      Seminal Vesicle Involvement (SVI) (13%)
• ·      No positive lymph nodes or signs of progressive disease
• ·      PSA doubling time> 6 months (74%)
• ·      Gleason 7-10 (76%)
• ·      Median age – 67 years
•     Low Risk = Gleason 7, negative margins, PSADT>8 months and no SVI
•     High Risk= all others

The treatment consisted of:

• ·      External beam RT: 66 Gy to prostate bed ± pelvic lymph node radiation
• ·      369 patients received 6 months of goserelin, 374 received no hormone therapy

After a median of 112 months of follow up, the results were:

10-year  progression-free survival was 46% lower without ADT (HR=0.54)

• HR=0.47 among low risk patients     
• HR=0.56 among high-risk patients

     10-year metastasis-free survival was 75% with ADT,  69% without ADT (HR=0.73)

      Acute toxicities: 89% with ADT, 79% without ADT

·      No difference in Grade 3 acute toxicities

·      No difference in late toxicities

Based on this, the authors conclude, “RT+HT could be considered as the standard in this situation.” The authors are of course privy to data we have not yet seen. It behooves us to further explore this rich source of information, to the extent that the sample size permits, to help determine which patients are most likely to benefit from the combined modality. There may be some with, say, low Gleason score, Stage pT2, small positive margins, and low, slowly rising PSA levels who do not need ADT, or may even be safely watched. Others, with evidence of systemic micrometastases may benefit from even more extensive ADT (see below).

Timing of the initiation of SRT is an issue in this study. SRT was delayed until there was a confirmed indication of biochemical recurrence (PSA≥0.2 ng/ml). However, three randomized clinical trials published after this study started have confirmed the benefit in biochemical control of beginning radiation much sooner in PSA progression. It is unclear whether ADT would have been as beneficial or necessary at all had therapy begun when PSA reached 0.03 ng/ml on an ultrasensitive test.

Several randomized clinical trials have demonstrated a benefit to adding ADT to RT for first-line treatment of advanced prostate cancer. There have been several retrospective analyses that hinted that ADT could enhance the effectiveness of SRT as well. Cortés-González et al. in Sweden reported a 4-year biochemical no evidence of disease of 63% among men treated with 3 months of hormone therapy before SRT. Choo et al. in Toronto reported a 7-year freedom from relapse rate of 79% among men treated with 2 years of ADT after SRT. Pai et al. in Vancouver reported 5-year biochemical disease-free survival of 80% if they had adjuvant radiation with ADT pre-treatment, but 67% without the pre-treatment; and 62% if they had salvage radiation with ADT pre-treatment, but only 27% without the pre-treatment.

An earlier randomized clinical trial (RTOG 9601) proved that 2 years of anti-androgen therapy with bicalutamide improved the 7-yr freedom from progression to 57% compared to 40% for SRT alone. Incidence of metastases was also significantly reduced, and toxicity was about the same, except for an increase in gynecomastia and liver toxicity. Howard Sandler added this comment:

"So, in my view, 9601 endorses ADT or bicalutamide for men with elevated PSAs after surgery, but most rad oncs have a PSA threshold: if the PSA is low, then RT alone, if the PSA is high, RT+ADT. There is variation in this threshold. My own personal threshold is 0.5 ng/mL."

Further evidence for the systemic effect of ADT came from a retrospective study by Soto et al. at the University of Michigan. They reported that concurrent ADT was beneficial only among those who had been originally diagnosed as high risk (the group most likely to evince micrometastases).

Among the factors yet to be learned are the optimum duration and timing of the added ADT. In a retrospective study, Jackson et al. at the University of Michigan reported 5-year incidence of distant metastases was 6% if they received more than 12 months of additional ADT after SRT, but 23% if they received less than 12 months of additional ADT. In fact, every month of ADT was associated with a 10% reduction in biochemical failure, distant metastases, and mortality.

(Update 3/21/2019) Fossati et al. identified 3 risk factors that determined optimal duration of adjuvant ADT with salvage RT:

• Stage ≥ pT3b
• Gleason score ≥ 8
• PSA≥ 0.5 ng/ml

Men with 2 or 3 risk factors benefited from up to 3 years of adjuvant ADT; men with 1 of the 3 benefited from up to 12 months of ADT; men with no risk factors did not benefit from adjuvant ADT.

This study raises many important questions about the use of ADT with SRT:

• ·      Is it beneficial when radiation doses above 70 Gy are used, or with hypofractionated SRT?
• ·      Is it beneficial when started sooner?
• ·      What are the effects of adding ADT on long-term sexual function?
• ·      Are there subsets of patients who are more likely to benefit than others?
• ·      Are there biochemical markers (e.g., Decipher™ or CellSearch™) that may be used to identify patients more likely to benefit?
• ·      Should ADT be started neoadjuvantly (before SRT)? Should ADT be used concurrently and adjuvantly?
• ·      Is the optimum duration of ADT use related to the patient’s pathological findings – pre-treatment PSA, Gleason score, stage, and positive margins?
• ·      Would outcomes improve with the expansion of the treatment field to include pelvic lymph nodes, and in which patients?
• ·      Would outcomes improve through the detection and boosted treatment of metastases identified using multiparametric MRIs or PET scans?
• ·      Would immune enhancement (e.g., Provenge, Leukine, Yervoy, Keytruda) improve outcomes?
• ·      Would outcomes improve still further with adjuvant docetaxel, as demonstrated recently by RTOG 0621?
• ·      Would stronger forms of androgen deprivation (e.g., Zytiga or Xtandi) improve outcomes?

There are a couple of randomized clinical trials that will help answer more of the outstanding questions. RADICALS-RT includes arms that are getting no ADT, short-term ADT, and long-term ADT. RTOG 0534 includes arms that are getting SRT with no ADT, short-term ADT, and short-term ADT with pelvic lymph node radiation.

GETUG-AFU 16 represents an important advance in our knowledge of the interaction of short-term ADT with salvage radiation. However, before subjecting every man getting salvage radiation to ADT, we have to learn which patients are most likely to benefit, and the optimum treatment protocol.