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.

Androgen deprivation therapy (ADT) and escalated dose in radiation therapy (RT)

Several recent studies shed light on the optimal use of androgen deprivation therapy (ADT) used in conjunction with radiation therapy (RT), including new learning about timing of ADT, RT dose, and their use in various risk categories.

When external beam radiation doses of around 70 Gy were used in the 1990s, it was shown that androgen deprivation therapy (ADT) used with it could improve oncological outcomes. However, it was not at all clear that ADT provided any additional benefit when higher doses radiation of about 80 Gy were used. DART 01/05 (Zapatero et al.) was a randomized clinical trial to determine the optimal duration of ADT supplementation.

DART 01/05 was a multi-institutional Spanish trial among intermediate and high risk men receiving primary treatment with 3D conformal radiation therapy (3DCRT) between 2005 and 2010. The patients were randomized to receive either 4 months (short term) or 28 months (long term) of ADT.

• Everyone received 2 months of ADT before and 2 months during their 3DCRT
•  Everyone received goserelin, an LHRH agonist, throughout, and also received 2 months of anti-androgen therapy (bicalutamide or flutamide) at the beginning.
•  173 patients received short-term ADT, 171 patients received long-term ADT

o   90 were high risk on long-term ADT

o   91 were high risk on short-term ADT

o   83 were intermediate risk on long-term ADT

o   78 were intermediate risk on short-term ADT

• Everyone received a median radiation dose of 78 Gy.

The 5-year outcomes were as follows:

• Biochemical disease-free survival was significantly better with long-term compared to short-term ADT: 90% vs. 81%

o   The difference was only significant among high risk patients: 88% vs. 76%.

•  Metastasis-free survival was significantly better with long-term compared to short-term ADT: 94% vs. 83%.

o   The difference was only significant among high risk patients: 94% vs. 79%.

• Overall survival was significantly better with long-term compared to short-term ADT: 95% vs. 86%.

o   The difference was only significant among high risk patients: 96% vs. 82%.

o   There were 5 deaths due to prostate cancer, all among men on short-term ADT.

• There were no significant differences in acute or late term rectal or urinary toxicities.

The authors conclude:

“Compared with short-term androgen deprivation, 2 years of adjuvant androgen deprivation combined with high-dose radiotherapy improved biochemical control and overall survival in patients with prostate cancer, particularly those with high-risk disease, with no increase in late radiation toxicity. Longer follow-up is needed to determine whether men with intermediate-risk disease benefit from more than 4 months of androgen deprivation.”

For high risk patients, at least, this establishes that dose-escalated RT with long-term ADT is preferable to short term. It leaves several open questions about optimum radiation treatment for this group:

• What is the optimal duration of ADT? We know from an earlier randomized clinical trial (Nabid et al.) that 18 months of adjuvant ADT is as good as 36 months, even with lower dose RT. So the optimal duration is somewhere between 6 months and 18 months.
•  Is IMRT with a brachytherapy boost preferable, and is that enhanced by ADT? (See this link)
•  Is SBRT monotherapy preferable, with or without adjuvant ADT? (This was discussed in a recent article.)
• What is the effect on erectile function?
• Should the pelvic lymph nodes be treated as well? This is the subject of an ongoing clinical trial.

Another randomized clinical trial presented at the Genitourinary (GU) Conference found more support for the addition of ADT to RT for intermediate risk patients. While DART 01/05 looked at long-term vs, short-term ADT with RT and found no difference for the intermediate risk subset, Nabid et al. looked at short-term vs. no additional ADT with RT for intermediate risk patients. They also examined the effect of radiation dose.

Their study consisted of 600 intermediate risk men treated with external beam radiation at several hospitals in Quebec between 2000 and 2010. The 3 arms of their study were treated under the following protocols:

1.    Arm 1: 6 months of ADT + 70 Gy of RT
2. Arm 2: 6 months of ADT + 76 Gy of RT
3. Arm 3: 76 Gy of RT

Those who received ADT were treated with 6 months of both goserelin and Casodex (bicalutamide) beginning 4 months before their RT began. After a median follow up of 76 months, the researchers found that:

• Biochemical failure was significantly higher in Arm 3, but not statistically different between arms 1 and 2.

o   Arm 1: 12.5%

o   Arm 2:   8.0%

o   Arm 3: 21.5%

• 10-year disease-free survival was significantly lower in arm3, but not statistically different between arms 1 and 2.

     

o   Arm 1: 77%

o   Arm 2: 90%

o   Arm 3: 64.5%

• 10-year overall survival was not statistically different between any of the arms.

o   Arm 1: 64%

o   Arm 2: 70%

o   Arm 3: 78% 

• There were only 6 deaths (1%) attributable to prostate cancer, not enough to discern a difference among treatment arms.

The authors conclude:

“In patients with intermediate risk prostate cancer, the use of short term ADT in association with RT, even at lower doses, leads to a superior biochemical control and DFS as compared to dose-escalated RT alone. These outcomes did not translate into an improved overall survival.”

I hope the authors will attempt a sub-group analysis to determine if there were significant differences when favorable vs. unfavorable intermediate risk (see below) is taken into account. It will also be interesting to look at the side effect profile in the 3 arms.

A randomized clinical trial (RTOG 0126) of low dose (70 Gy) vs. high dose (79 Gy) radiation in intermediate risk patients, but without ADT, found improvements in the risk of biochemical failure, distant metastases, and time to local progression in those treated with the higher dose. However, they found no improvement in overall survival with 10 years of observation. Those treated with the higher dose did experience higher rates of urinary and rectal toxicity, however.

One must consider whether the higher rates of urinary and rectal toxicities are still applicable with modern IGRT/IMRT techniques. The men in the above studies were treated with 3DCRT – an older, less precise radiotherapy. As often occurs with long-term clinical trials of radiation therapies, the results may become irrelevant by the time they are reported because of technological advances.

I think 10 years is too short a follow-up period to detect significant differences in survival among intermediate risk men, and especially among favorable intermediate risk men. It also begs the question of whether those men require immediate treatment at all. Some of the sub-groups, including some who are older with co-morbidities, some with favorable PSA kinetics, low volume of cancer, and some with Gleason score≤ 3+4, may be better off with expectant management.

In contrast to the lack of survival benefit to the escalated dose found in RTOG 0126, a retrospective analysis reported at the GU Conference by Kalbasi et al. looked at 12,848 low risk patients, 14,966 intermediate risk patients, and 14,587 high risk patients After a median 73 months of follow up, they found a significant dose response for both the intermediate risk and the high risk patients, but not the low risk patients. For every 2 Gy increase in dose, there was a reduction in the hazard of death of 9% and 7% among the intermediate and high risk patients, respectively.

Perhaps sub-group analysis will explain the difference in the dose response between the two studies. I will report on both further when more detailed findings become available.

I don’t think it will come as any surprise that radiation added to androgen deprivation has better oncological outcomes than androgen deprivation alone. In a randomized clinical trial among 1,205 locally advanced prostate cancer patients treated between 1995 and 2005 with ADT and with or without low dose (64-69 Gy) RT, Mason et al., with median 8 years of follow-up, found that the addition of RT reduced prostate cancer mortality by about half.

Favorable vs. Unfavorable Intermediate Risk

In an earlier article, we noted that Dr. D’Amico raised a caution that the results may look very different if the intermediate risk men were divided into favorable and unfavorable groups. It may be that with further follow-up time, significant differences will appear among the intermediate risk men, and particularly among those with unfavorable features. In a retrospective study by Castle et al. where intermediate risk men were divided into favorable or unfavorable intermediate risk, favorable risk patients had no discernable benefit from the addition of ADT. Unfavorable intermediate risk patients had significantly higher 5-yr freedom from failure if they also received ADT, 74% vs. 94%, respectively. Similarly, Edelman et al. found that ADT combined beneficially with RT only in intermediate risk patients with GS 4+3, more than 50% positive cores, or multiple intermediate risk factors.

Another retrospective study by Keane et al. confirming that finding was presented at the recent Genitourinary Conference. They analyzed the oncological outcomes of 2,668 intermediate risk men (71% favorable, 29% unfavorable) treated between 1997 and 2013 with dose-escalated RT and with and without adjuvant ADT (median 4 months). After a median follow-up of 7.8 years, they found that there was a significant amelioration of the risk of prostate cancer-specific mortality among the unfavorable risk patients who also received ADT, but adding ADT did not make a difference to prostate cancer-specific mortality in those men categorized as favorable intermediate risk.

ADT Sequencing

The conventional wisdom is that neo-adjuvant ADT (ADT started at least two months before the start of radiation) and ADT given concurrently with RT have a different functional benefit from adjuvant ADT (ADT given after the completion of RT). Neoadjuvant and concurrent ADT is thought to radiosensitize the cancer to the radiation treatment, while the adjuvant ADT is thought to function as “clean-up,” killing off small amounts of hormone-sensitive stray cancer cells that may already be systemic. A new study by Weller et al. is calling that model into question.

They analyzed the records of intermediate and high risk patients treated from 1995 to 2002 who had either neoadjuvant and concurrent ADT with their dose-escalated RT (311 patients) or only adjuvant ADT immediately after their dose-escalated RT (204 patients). Ten-year biochemical recurrence-free survival was 61%, distant metastasis-free survival was 80%, and overall survival was 66%. There were no significant differences in any of those measures based on the sequencing of ADT.

The authors conclude:

“the synergy between RT and androgen deprivation is independent of the sequencing of both modalities and the initiation of RT does not need to be delayed for a course of neoadjuvant ADT.”

I think these findings have to be confirmed by a randomized clinical trial. It raises interesting questions about the way ADT and radiation interact to kill cancer cells, perhaps supporting the hypothesis that ADT sustains the immune response to the radiation-induced increase in cancer antigens. If the abscopal effect turns out to be of major importance in the ADT/radiation killing of cancer cells, various immunotherapies, like Provenge, Prostvac, Yervoy, and Keytruda, may improve the oncological benefits still further.