Optimal duration of adjuvant ADT depends on the type of radiation used for high-risk patients

No one wants to have androgen deprivation therapy (ADT), even if it is for a limited time. It has been known for a long time that it improves oncological outcomes when given with ("adjuvant to") radiation therapy in patients with high-risk prostate cancer. Several randomized clinical trials (RCTs) have tried to find the best duration to use it, but it is difficult to arrive at reliable optimization points- it would involve varying the duration for a large number of high risk patients. Kishan et al. have taken an innovative approach to solving this problem by combining several RCTs and a multi-institutional observational study. Unlike typical "meta-analyses," they compared similar patients across three studies.

The three studies they used in their analysis were:

1. The high-risk patients in the DART 01.05 GICOR RCT (see this link), which randomized patients to 28 months or 4 months of adjuvant ADT in patients getting high dose external beam radiation (EBRT-only). They found that 28 months is better than 4 months, but is there a duration that is less than 28 months for EBRT-only?
2. The patients in the TROG 03.04 RADAR RCT (see this link), which randomized patients to 18 months or 6 months of adjuvant ADT in patients getting varying doses of EBRT or high dose rate brachy boost therapy (BBT). They found that 18 months is better than 6 months for BBT, but is there a duration that is less than 18 months for BBT?
3. The patients in a multi-institutional (retrospective, non-randomized) study who received varying durations of adjuvant ADT and EBRT-only or brachy boost therapy for their high risk PCa (see this link).

They used distant metastasis-free survival (DMFS) as the endpoint of interest because it has been found to correlate well with eventual overall survival. They went back to the original patient-level data to extract comparable patients when comparing them across studies. This retained many of the advantages of each of the three studies. While this innovative approach does not constitute the highest level of evidence (Level 1), it offers a degree of reliability that goes beyond simple observational studies.

They used two statistical methods to look at the data. In one analysis, they divided the durations into three parts: 

• ≤6mo.
• >6 - 18 mos
• >18 mos

In another analysis (called "cubic splines") they found the best fit for the continuous data. Both analyses led to similar conclusions.

The best estimates for the best minimum adjuvant ADT duration are:

• at least 26.3 months for EBRT-only
• at least 12 months for BBT

But, one might object, didn't Nabid's PCS IV trial show that 18 months is as good as 36 months (see this link)? Kishan points out that only about half of the cohort in that trial who were supposed to get 36 months of ADT actually got that much. And nearly a quarter of the 36-month cohort actually received less than 21 months. The only data we've seen so far has been analyzed by the dose they were intended to get, not by what they actually got. Also, why were the drop-out rates so high? The DART RCT had 95% compliance with the full 28 months, even though the radiation doses given were much higher.

There is a trade-off: BBT can come with severe late-term urinary side effects (among 19% in the ASCENDE-RT RCT), while the late-term urinary side effects are milder for EBRT-only (only 2.5% in DART). Only the patient can decide if he is willing to take on 12 months of ADT with BBT vs over twice as long for EBRT-only, given the higher expected radiation toxicity with BBT.

Which is better: EBRT+2 years of ADT or BBT+1 year of ADT?

Patel et al. looked at the use of the two therapies at many of the top cancer centers. They found there was no significant difference in the occurrence of distant metastases or in prostate cancer-specific survival.

There are several unanswered questions:

• As we have seen (see this link), brief intense use of abiraterone or other advanced hormone therapy may obviate the need for longer ADT.
• Decipher genomic analysis may indicate which patients may be able to get away with less hormone therapy, and which need more. The PREDICT-RT RCT will eventually answer this question.
• Does SBRT monotherapy or HDR brachy monotherapy still require adjuvant ADT? Those therapies can have almost as high a biologically effective dose as BBT but with fewer side effects. This study suggests that 12 months of ADT is beneficial with even the highest dose radiation, but future clinical trials will give a more reliable answer.
• Standard-of-care dictates 2-3 years of adjuvant ADT when enlarged pelvic lymph nodes are found by CT or MRI. What is the optimum duration when cancerous pelvic lymph nodes are only detected with a PSMA PET scan and not by CT? What about when they are too small to be detected by any kind of imaging, and their presence is only suggested by risk characteristics?
• What duration of adjuvant ADT minimizes biochemical recurrence-free survival and the need for any salvage treatment?
• Will these estimates hold up if tested in an RCT?

Importance of Adding ADT to Brachy Boost Therapy for Men with Unfavorable-Risk Prostate Cancer

Last month, we looked at Level 1 evidence (highest level, superseding all previous studies) that for unfavorable risk patients, brachy boost therapy (BBT) [external beam therapy (EBRT) with a brachytherapy boost to the prostate] has better results when accompanied by 18 months of androgen deprivation therapy (ADT). (see this link)

Now a meta-analysis has reaffirmed that finding. The two studies were probably submitted for publication at about the same time, which explains why the meta-analysis doesn't include data from RTOG 01.03 RADAR. In the Jackson et al. meta-analysis (and Medpage summary), there were:

• 6 randomized trials of EBRT with or without ADT comprising 4,663 patients.
• 3 randomized trials of EBRT with or without a BBT comprising  718 patients.
• One of those trials included ADT, the other two did not

Their analysis found that ten-year overall survival was:

• improved by 30% by the addition of ADT to EBRT
• not improved by the addition of BBT to EBRT (at least when ADT was not included)
• The addition of ADT had a bigger impact than the addition of BBT
• The trial that included both ADT and BBT had the best results

Because this meta-analysis included trials with men from different risk levels, it gives no direction about which therapy is best for favorable- vs unfavorable-risk men. DART 01/03 GICOR proved that adjuvant ADT only provides an added benefit to EBRT in high-risk men (vs intermediate risk men). Furthermore, BBT did not benefit and did add toxicity to favorable-risk patients (see this link).

Some of the trials did not include radiation doses now considered curative. It also did not look at ADT duration.

Long-term adjuvant ADT improves results of brachy boost therapy in unfavorable-risk prostate cancer patients

TROG 01.03 RADAR, begun in 2003, was a  (partly) randomized clinical trial to help optimize therapy of unfavorable-risk patients. It explored such topics as use of Zometa, radiation dose escalation, and optimal duration of androgen deprivation therapy (ADT) when given along with ("adjuvant" to) radiation therapy (RT).

• Zometa did not delay progression, which is similar to the STAMPEDE trial finding among men with metastatic hormone-sensitive prostate cancer when it was used without Celebrex. 
• The external-beam radiation (EBRT) doses they explored (66 Gy, 70 Gy and 74 Gy) were below today's standard of care (78 Gy-82 Gy), so have become irrelevant to current practice. 
• The assignment to various radiation doses was not randomized. 
• The benefit of long-term ADT (28 months vs 4 months) with dose-escalated EBRT in unfavorable-risk patients was proved by the DART 01/05 GICOR trial. 

Based on the Kishan et al. study, brachy boost therapy may be the preferred treatment option for high-risk patients So we will turn our focus to the only outstanding question that this major trial can still shed light on - what duration of adjuvant ADT is necessary when unfavorable-risk patients are treated with high dose rate brachy-boost therapy (HDRBBT)?

Joseph et al. reported the 10-year outcomes of the TROG 01.03 RADAR trial conducted at 24 sites in Australia and New Zealand. From 2003 to 2007, patients were randomized on 6 vs 18 months of adjuvant ADT . There were 1,051 evaluable unfavorable-risk patients defined as:

• Stage T2b-4 or
• Stage T2a and Gleason score≥7 and PSA≥10 ng/ml
• NCCN risk groups: 31% unfavorable intermediate-risk, 66% high-risk
• Patients with positive pelvic lymph nodes (stage N1) or distant metastases (stage M1) on a bone scan/CT were excluded

The HDRBBT treatment given to 237 patients consisted of:

• 46 Gy in 23 treatments of EBRT followed by 19.5 Gy in 3 HDR brachy treatments (biologically equivalent to 88 Gy if given as EBRT-only)
• All patients received 6 months of adjuvant ADT (Lupron) starting 5 months before EBRT 
• Half were randomized to get 12 extra months of ADT (total =18 months) 
• Pelvic lymph nodes were not treated

Distant progression (radiographic progression on a bone scan/CT) was the primary endpoint. The 10-year outcomes for those receiving HDRBBT were:

• 20% distant progression (25% less than 74 Gy EBRT)
• 2% local progression (71% less than 74 Gy EBRT)
• 15% bone progression (31% less than 74 Gy EBRT)
• 9% prostate cancer-specific mortality (25% less than 74 Gy EBRT)
• 23% all cause mortality (31% less than 74 Gy EBRT)
• Distant progression was reduced by 39% by the longer ADT treatment. It was statistically significant even after adjustment for potentially confounding risk factors.
• Longer ADT was beneficial independent of RT dose, whether EBRT or HDRBBT
• 13% of men receiving HDRBBT suffered urethral strictures vs 4% of men receiving 74 Gy EBRT (for full toxicity data, see this report)
• The cumulative incidence of transition to castration resistance was significantly lower in men receiving 18 months of adjuvant ADT with RT (in an earlier report)

This establishes the importance of adding long-term (18 months) ADT for all unfavorable risk patients receiving radiation as a primary treatment. The adjuvant ADT gave better outcomes independent of the radiation dose. The Nabid et al trial proved that 18 months is as useful as 36 months in high-risk patients. But rather than slavish adherence to a single number, NCCN recommends 18 months to 3 years of adjuvant, at the discretion of the doctor.

The patient may wish to get more if:

• there are multiple high-risk features (e.g., GS9-10, PSA>20, T3/4, PNI, rare histology, genomic risk)
• there is suspicion of lymph node metastases, especially from advanced PET scans
• side effects are very tolerable

The patient may wish to get less if:

• there are lower risk features (e.g., GS 6-8, PSA<10, T2, no genomic risk)
• advanced PET scans (Axumin or PSMA) are negative
• side effects are onerous
• treatment is entirely extremely hypofractionated (HDR brachy or SBRT monotherapy)
• an additional systemic treatment (e.g., docetaxel, Zytiga, Xtandi, Erleada, or Nubiqa) is used experimentally

In an earlier observational meta-analysis (see this link), adjuvant ADT did not seem to add benefit to brachy boost therapy. This once again shows the limitation of observational studies. Only randomized clinical trials can provide the definitive proof we desire for decision-making.

Some patients think they can delay the transition to castration-resistance by eliminating or reducing the amount of ADT used with their RT. This shows that does not happen. Castration resistance is a consequence of genomic breakdown that always occurs as the cancer evolves. It may be facilitated by eliminating the hormone-sensitive cells and leaving only castration-resistant cells (this is called "competitive release"). By eliminating cancer cells as early as possible (before metastases have been detected) using HDRBBT and long-term adjuvant ADT, there is an opportunity to cure the disease. We are learning that cancer cells signal other cancer cells via extracellular vesicles to become like them. Even if it does not cure the patient, the profound reduction of the cancer load has a bigger effect on castration resistance than drug resistance does. This phenomenon was also noted in the TOAD randomized clinical trial (see this link). After there are metastases, an "evolutionary" personalized strategy (like this one) may be preferable.

Is whole pelvic radiation needed for primary treatment of Gleason 9/10?

Whether whole pelvic radiation therapy (WPRT) is beneficial for men newly diagnosed with Gleason 9/10 (Grade Group 5) is controversial. There is an ongoing randomized clinical trial (RTOG 0924) that will have results by 2027 at the earliest, but it includes intermediate and high-risk patients, very few of whom will have Gleason 9/10. Two previous randomized clinical trials (RCTs) gave conflicting results: RTOG 9413 showed a benefit to WPRT combined with ADT started before and continued through radiation treatment, while GETUG 01 found no benefit. However, neither RCT delivered doses of radiation that would be considered adequate by today's standards (70 Gy vs 80 Gy).

Sandler et al. analyzed the databases of 12 major institutions that treated 1170 Gleason 9/10 patients between 2000 and 2013.

• 299 received external beam radiation therapy (EBRT) boost to the prostate + WPRT
• 435 received EBRT only to the prostate + a small margin around it
• 320  received a brachytherapy boost (BBT) to the prostate + WPRT
• 116 received BBT only to the prostate + a small margin around it
• Patients were matched on age, T stage, PSA, Gleason score, and analyzed by ADT duration

After median follow-up of 5.6 years, 5-year biochemical recurrence-free survival (bRFS) was:

• 88% for BBT+WPRT
• 78% for BBT alone
• 66% for EBRT+WPRT
• 58% for EBRT alone
• WPRT was significantly improved by BBT (Hazard Ratio = 0.5, p=0.02) but not by EBRT (HR=0.8, p=0.4))
• Neither distant metastasis-free survival nor prostate cancer-specific survival were significantly improved by WPRT

In interpreting these findings, patients should discuss the following considerations with their radiation oncologists.

Lack of long-term follow-up

As we have observed before (see this link), it can take 15 or more years until over half of high risk patients have detectable metastases (by bone scan/CT) or have succumbed to prostate cancer. In this study, only 35% of those getting EBRT alone had been diagnosed with distant metastases, and only 23% had died of prostate cancer. The rates for all other groups were smaller. As the data mature, we expect that the now-evident and statistically significant differences in biochemical failure will eventually result in higher rates of metastases and mortality.

Lack of local control with EBRT only

ASCENDE-RT proved that prostate cancer is better controlled in high-risk patients by a brachytherapy boost than by EBRT alone. Local control (of cancer in the prostate) is obviously required because the high grade cancer easily progresses and metastasizes from the prostate.

Lack of regional control with surgery

As we have seen, prostatectomy, even when followed by radiation (see this link) seems to provide inferior cancer control compared to BBT with WPRT. This may be because the salvage radiation dose to the prostate bed (usually only 66-70 Gy) is inadequate compared to the primary radiation dose (see this link).

Inadequate coverage/detection of pelvic lymph nodes

In the present study, patients received WPRT to the standard pelvic lymph nodes. We have seen that this is inadequate to reach  the cancerous pelvic lymph nodes in over 40% of patients (see this link). Current methods do not allow us to find most of the cancerous lymph nodes (see this link). While PET scans are not yet FDA-approved for high-risk patients (as they are for recurrent patients), there are a few available in clinical trials.

Inadequate dose to pelvic lymph nodes

The dose to pelvic lymph nodes is often about 45-50 Gy given in 1.8 Gy increments. If it's true that perfect cancer control is achieved only with doses around 80 Gy, this treatment may be inadequate to control some of the larger lymph node metastases. This may be especially true because lymph node metastases are not well-oxygenated (hypoxic). As PET/CTs and PET/MRIs become available for high-risk patients, it may become possible to target known lymph node metastases with higher doses. Another fertile area for investigative research is radiosensitization with hyperthermia (see this link).

Toxicity

In RTOG 0534, late Grade 2 or worse gastrointestinal toxicity occurred in 7% of those receiving WPRT. While this is higher than the 2% experiencing this degree of toxicity with prostate-only EBRT treatment, it is nevertheless at a low level. In a large non-randomized, retrospective study comparing WPRT to prostate-only radiation, Parry et al. found no difference in the 3-year cumulative incidence of gastrointestinal and urinary toxicity among high risk and locally advanced patients.

Because we may never have more reliable data, patients and their radiation oncologists must make this decision based on this study and judgement for the foreseeable future.

note: Thanks to Amar Kishan for allowing me to see the full text.

Can surgery+radiation+ADT provide equal outcomes to brachy boost therapy +ADT in high risk men?

As we saw (see this link) among men with Gleason 9 or 10, brachy boost therapy (BBT: external beam radiation with a brachytherapy boost to the prostate) was shown to provide better oncological outcomes (10-year metastasis-free survival and 10-year prostate cancer-specific mortality (PCSM)) compared to surgery (RP) or external beam radiation (EBRT) alone. Some researchers argue that the comparison was unfair. In that study, 43% of the RP patients received adjuvant or salvage radiation, and virtually all of the BBT patients received 1 year of adjuvant ADT. What if ALL of the RP patients were to receive radiation and ADT?

Tilki et al. did a retrospective study to answer that question. They looked at two groups of Gleason 9/10 patients treated at two institutions between 1992 and 2013:

• 559 men received RP+pelvic lymph node dissection (PLND) at the Martini-Klinik Cancer Center in Hamburg
• 88 received adjuvant EBRT
• 49 received adjuvant ADT
• 50 received both (called MaxRP)
• Median ADT duration - 8.6 months in 49 men with negative lymph nodes
• Median ADT duration - 14.5 months in 39 men with positive lymph nodes

• 80 men received BBT+ADT (called MaxRT) at the Chicago Prostate Center
• Median ADT duration - 6 months

After 5.5 years of median follow-up for MaxRT and 4.8 years of median
follow-up for those receiving RP, they found that the risk of PCSM compared to MaxRT was:

• 2.8 times greater for any RP (statistically significant)
• 0.5 times less for RP+adjuvant EBRT (not statistically significant)
• 3.2 times greater for RP+adjuvant ADT (statistically significant)
• 1.3 times greater for MaxRP (not statistically significant)

The 5-year PCSM was:

• 2% for MaxRT
• 22% for any RP (significantly higher than MaxRT)
• 4% for RP+adjuvant EBRT (not significantly different from MaxRT)
• 27% for RP+adjuvant ADT (significantly higher than MaxRT)
• 10% for MaxRP (not significantly different from MaxRT)

They computed a 76% chance ("plausibility index") that the PCSM was plausibly the same for MaxRT vs. MaxRP.

Kishan et al. supplied numbers from his study that are more directly comparable. They are shown in the table below.

Study	Tilki	Kishan
Sample size	BBT: 80 RP+EBRT: 88 RP+ADT: 49 RP+EBRT+ADT: 50	BBT: 436 RP+EBRT: 272 RP+ADT: 175
ADT duration (median)	BBT: 6 months RP (N1): 14.5 mos. RP (N0): 8.6 mos.	BBT: 12 months
Among RP,% N1	44%	17%
5-year % PCSM	RP (any): 22% BBT: 2%	RP (any): 12% BBT: 3%
Adjusted PCSM Hazard Ratio compared to BBT:	RP+ADT: 3.2 RP+EBRT: 0.5 (not sig.)	RP+ADT: 3.2 RP+EBRT: 2.0

We see that the two studies are really not comparable in some respects. The Kishan study was much larger, and was done among many of the top institutions. The Hamburg patients had a much higher percent of positive lymph nodes, and their mortality was twice as high as in the Kishan study. The Chicago patients only got half as much ADT vs. the Kishan study. Importantly, the Kishan study found that RP+EBRT had PCSM that was twice as high as BBT, while the Tilki study showed no statistically significant difference.

Another important aspect was not reported in either study - the toxicity of treatment. We know that surgery plus radiation has worse urinary and sexual side effects compared to surgery alone.BBT carries risk of higher late-term urinary side effects compared to EBRT alone.

Until we have a randomized clinical trial of BBT vs MaxRP, we will never have certainty, but for now, the Kishan study better reflects expected outcomes of these therapies at top institutions.