THE "NEW" PROSTATE CANCER INFOLINK

For the first time, a randomized clinical trial (GETUG-AFU 16) has proved that adding a short course of androgen deprivation therapy (ADT) to salvage radiation therapy (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. conducted a multi-institutional study in France on 743 patients with the following characteristics:

• Randomized for sRT ± ADT between 2006 and 2010
• Undetectable PSA post-prostatectomy
• PSA ≥ 0.2 ng/ml and PSA doubling time > 6 months at relapse (74 percent)
• Gleason score 7 to 10 (76 percent)
• Median age, 67 years

The treatment consisted of:

• External beam RT: 66 Gy to prostate bed ± pelvic lymph node radiation
• 369 patients randomized to receive 6 months of goserelin acetate/Zoladex; 374 received no hormone therapy

After a median of 63 months of follow up, the results were:

• 5-year progression-free survival: 80 percent with ADT, 62 percent without ADT
• Too early to assess impact on overall survival
• Acute toxicities: 89 percent with ADT, 79 percent without ADT
• No difference in Grade 3 acute toxicities
• No difference in late toxicities

Based on this, the authors conclude that,

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).

As is often the case with long-term clinical trials, the findings become increasingly irrelevant over time because standard practices and technologies have evolved. The radiation dose used in this clinical trial, 66 Gy, is significantly below the level of 70 Gy often considered to be necessary. According to an analysis by King and Kapp, an increase of 4 Gy in sRT dose is likely to result in an increase in biochemical control of 15 percentage points. This alone would have eliminated much of the gap seen in this study. It is unclear whether ADT would still have been beneficial had the dose been escalated.

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 percent 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 percent among men treated with 2 years of ADT after sRT. Pai et al. (in Vancouver) reported 5-year biochemical disease-free survival of 80 percent if they had adjuvant radiation with ADT pre-treatment, but 67 percent without the pre-treatment; and 62 percent if they had salvage radiation with ADT pre-treatment, but only 27 percent without the pre-treatment.

An earlier randomized clinical trial (RTOG 9601) proved that 2 years of anti-androgen therapy with bicalutamide improved the 7-year freedom from progression to 57 percent compared to 40 percent 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. A follow-up analysis showed that the benefit was restricted to those with lower PSA and negative margins. This suggests that the role of ADT may be in destroying micrometastases, perhaps in conjunction with an abscopal effect from the radiation.

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 percent if they received more than 12 months of additional ADT after sRT, but 23 percent if they received less than 12 months of additional ADT. In fact, every month of ADT was associated with a 10 percent reduction in biochemical failure, distant metastases, and mortality.

The new study by Carrie et al. 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. The RADICALS radiation therapy trial 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.

Editorial comment: This commentary was written by Allen Edel for The “New” Prostate Cancer InfoLink.

Filed under: Living with Prostate Cancer, Management, Treatment | Tagged: ADT, androgen, deprivation, post-surgery, radiation, salvage |