Very early salvage radiation has up to 4-fold better outcomes and saves lives

Another  subject that has come up a lot recently is when to have salvage radiation. It is always a pressing decision for those 30% of prostatectomy patients who have detectable PSA after prostatectomy. We have seen (see this link) that a low PSA on an ultrasensitive PSA test, as low as 0.03, can be a predictor of full biochemical recurrence later. This latest analysis of this subject looked at how treating sooner rather than later was associated with better cancer control and survival.

Abugharib et al. examined the records of 657 men who had salvage radiation therapy (SRT) from 1986 to 2013 at the University of Michigan and the University of Texas Southwestern. They were all discovered to have detectable PSA following prostatectomy. Researchers were looking for evidence to confirm or contradict their hypothesis that earlier SRT had better outcomes.

They defined "earlier" in two ways:

1. At a lower PSA. Because of the treatment dates, there was relatively little data from ultrasensitive PSA tests. They divided PSA at the time of SRT into three categories:

• 0.01-0.2 ng/ml - the "very early salvage" cohort
• >0.2 - 0.5 ng/ml - the "early salvage" cohort
• >0.5 ng/ml - the "later salvage" cohort (0.5 was selected because the median PSA was 0.4 ng/ml)

2. At an earlier time from completion of prostatectomy

• < 9 months   
• 9-21 months
• 22-47 months
• > 48 months

They looked at "outcomes" in four ways:

1. freedom from biochemical recurrence (PSA> 0.2 ng/ml) after SRT
2. freedom from starting salvage, life-long androgen deprivation therapy (ADT) after SRT
3. freedom from detectable metastases after SRT
4. prostate cancer specific survival

After a median follow-up of 9.8 years, they found:

• The time in months since completion of prostatectomy had no bearing on any of the outcomes.
• The PSA at which they were treated has a major impact on all outcomes.
• The "early salvage" group had outcomes that were about twice as poor as those who had "very early salvage." This was true after correcting for all the variables (like Gleason score and positive margins) that would have made a difference.
• The "later salvage group" had outcomes that were about four times as poor as those who had "very early salvage." This was true after correcting for all the variables (like Gleason score and positive margins) that would have made a difference.
• 91% of the variance in biochemical recurrence after SRT was explained by the PSA at which patients were treated.
• Adjuvant ADT, which was given to 24% of patients for a median of 6 months (range 4-24 months), was significantly associated with freedom from biochemical recurrence after SRT. There were 40% fewer failures. 

Researchers did not have data on PSA doubling time and velocity, and the number who had persistently elevated PSA, all of which almost certainly would affect outcomes. Perhaps such other variables as the length of the positive margins and the Gleason score there ought to be incorporated into a fuller analysis.

Patients who were treated at an early sign of detectable PSA  (0.2-0.5) were twice as likely to develop metastases and die of prostate cancer as those who were treated at the earliest PSA (below 0.2). Those who waited for PSA to rise above 0.5 ng/ml were four times as likely to develop metastases and die from prostate cancer compared to those treated when PSA first became detectable.

We have three large randomized clinical trials proving that outcomes are diminished by about half by waiting rather than treating within the first 6 months, even before there are detectable PSAs (called adjuvant radiation). But few elect to have adjuvant radiation, and the number has been declining (see this link). To avoid overtreatment and protect patients from perhaps unnecessary side effects of SRT, early salvage has emerged as a compromise.

The authors point out that it may take 7 months or more for adequate healing of urinary and erectile complications (see this link). Also, this is an important decision for the patient, which he ought not make hastily. Yet here, more than in the primary therapy decision, very early action can save lives. As a compromise, they suggest early use of neoadjuvant ADT (prior to SRT) which could slow the cancer down and give tissues more time to heal. The extra time may help the patient recover better urinary function, if not erectile function.

They recommend,

"Our data would suggest potentially a traditional cut-off of 0.2 to define biochemical failure may be too late, and that at the first sign of a detectable PSA that SRT (or SRT + ADT) should be initiated."

This remains a difficult decision, and the patient with a detectable PSA after surgery should begin discussions with a good radiation oncologist as soon as possible. Age and comorbidities enter into the decision as well. Unfortunately at these low PSAs, even the most accurate of the new generation of PET scans are incapable of finding distant metastases that might help rule out those cases where SRT would be futile. Nomograms and Decipher scores may help in cases where the decision is equivocal.

EBRT works better with ADT for intermediate/high-risk prostate cancer

The EORTC trial 22991 compared EBRT + short-term ADT vs. EBRT alone in intermediate and high-risk men. The preliminary report by Bolla et al. was posted at the 2016 GU Conference. There are more details of the clinical trial available here. There were 819 patients in the European multi-institutional study:

• ·      407 received EBRT only, 403 received EBRT+6 months of ADT
• ·      Radiation dose: 70, 74, or 78 Gy (at discretion of each institution)
• ·      Pelvic node radiation: at discretion of each institution
• ·      75% intermediate risk, 25% high risk

After a median follow-up of 7.2 years,

• ·      5-year biochemical progression-free survival was 82.5% with the ADT, 69.3% without it.
• ·      Improvement was irrespective of radiation dose.
• ·      5-year clinical progression-free survival was improved by 7.9 percentage points.
• ·      Late urinary toxicity was 5.9% with the ADT, 3.6% without it (not statistically significant)
• ·      Severe sexual function impairment was 27.0% with the ADT, 19.4% without it (statistically significant)
• ·      Symptoms of hormone treatment, sexual activity and functioning were impaired at 6 months with ADT, but there was no difference at 2 years.

The authors conclude:

“The addition of 6 months of medical castration to primary irradiation improves BPFS and PFS in intermediate- and high-risk localized T1b-cT2a N0M0 prostatic carcinoma with no persistent detriment on HRQOL or sexual function.”

Unfortunately, this preliminary report doesn’t break out the intermediate and high-risk men separately.

We have previously looked at the DART 01/05 clinical trial that proved that at escalated radiation doses, long-term (28 months) androgen suppression improved cancer control better than short-term (4 months), at least for high-risk men. The benefit of longer duration ADT was not established for intermediate risk men at 5-year follow-up.

Nabid et al. focused on intermediate risk men and found a clear benefit to adding 6 months of ADT rather than none (after 10 years of follow-up).

It now seems clear that short-term androgen suppression improves results in intermediate risk men, while longer androgen suppression is necessary in high risk men. It would be helpful to know whether the improvement in intermediate risk men was only among the subgroup classified as “unfavorable intermediate risk.” ADT seems to have a more powerful effect than radiation dose, but it is unclear if that effect is maintained with therapies like SBRT and brachy boost that treat with much higher biologically effective doses. We are getting closer to defining an optimal duration of adjuvant ADT by risk level, and future trials using genetic classification data may provide better definition.

ADT and radiation for first-line treatment of node-positive (N1) prostate cancer (STAMPEDE trial details)

In a previous commentary, we mentioned the early top-line results of the STAMPEDE trial, which demonstrated a benefit to whole-pelvic radiation and ADT for treatment of high risk prostate cancer when positive pelvic lymph nodes have been detected. We now have some additional details.

James et al. analyzed data from the control arm of the STAMPEDE trial. The control arm excluded patients with distant metastases and those who had previous treatment. All patients were high risk and were treated between 2005 and 2014 with a minimum of two years of ADT. At physician’s discretion, some were also treated with RT 6-9 months after the start of ADT. Patients with lymph nodes larger than 10 mm were typically staged as “node positive” (N1). Patient counts for this analysis were as follows:

• ·      N0 and RT – 121 patients – 43% received whole pelvic radiation
• ·      N0 and no RT – 46 patients
• ·      N1 and RT -  71 patients - 82% received whole pelvic radiation
• ·      N1 and no RT -  86 patients

Age, Gleason scores, and performance status were similar in all groups. Pre-treatment PSA was higher in patients who had RT, although the differences were not statistically significant. The planned radiation dose to the prostate and seminal vesicles was 74 Gy in 37 fractions or the equivalent hypofractionated dose. The planned dose to the pelvic lymph nodes was 46-50 Gy in 23-25 fractions or 55 Gy in 37 fractions. Increased doses were allowed if the physician was experienced in delivering nodal doses.

Although overall survival was measured, there was too little mortality as of this interim analysis to be worth reporting. Instead, the authors focused on 2-year Failure-Free Survival (FFS), defined as no biochemical recurrence, and no radiographically-detected progression among survivors. Patients would have been ADT-free for 12-15 months by that point, unless they showed early evidence of progressing.

Among the men with no detected nodal involvement( N0):

• ·      The 2-yr FFS was:

o   96% among men who received RT

o   73% among men who did not receive RT

• ·      Late GI toxicity was:

o   Proctitis: Grade 2: 7%, Grade 3: 2%

o   Diarrhea: Grade 2: 3%, Grade 3: 1%

o   Rectal ulcer: Grade 3: 1%

• ·      Late GU toxicity was:

o   Cystitis: Grade 2: 2%, Grade 3: 1%

o   Hematuria: Grade 2: 3%, Grade 3: 1%

Among the men with detected nodal involvement (N1):

• ·      The 2-yr FFS was:

o   89% among men who received RT

o   64% among men who did not receive RT

• ·      Late GI toxicity was:

o   Proctitis: Grade 2: 8%

o   Diarrhea: Grade 2: 6%

• ·      Late GU toxicity was:

o   Cystitis: Grade 2: 5%

o   Hematuria: Grade 2: 2%, Grade 3: 2%

Although this was a prospective study, patients were not randomized to receive RT or not, so there may be selection bias at work. The higher pretreatment PSA in the patients who did not get RT suggests that they may have been considered to be too far progressed to benefit from radiation. However, the benefit of RT was maintained even after adjustment for pretreatment PSA, age and Gleason score.

The planned radiation dose, 74 Gy, is lower than the 80 Gy now considered to be curative. The dose delivered to the pelvic lymph nodes is still within the standard of care. Although almost half of those with no nodal involvement were treated with whole pelvic RT, there was no analysis of benefit in that subgroup.

RT clearly delayed the time to relapse among high-risk patients, regardless of nodal status. The FFS curves continued to diverge after 2 years, indicating a lasting effect of treatment, at least out to 5 years post-treatment. Long-term toxicity was low among all patients who received RT.

Subject to the above caveat on selection bias, this early analysis indicates that men with high risk prostate cancer, whether they had detected nodal involvement or not, benefited from long-term ADT+RT. As there was little long-term toxicity attached to this decision, there seems little reason to withhold such treatment.

The questions mentioned in our earlier commentary continue to be important:

• What is the most appropriate radiation dose?
• Is there a limit to the number of infected nodes beyond which it is fruitless to use RT?
• Should simultaneous integrated boost RT be used on infected nodes?
• Can SBRT equal or improve the risk/benefit profile over IMRT?
• What is the best timing for neoadjuvant/concurrent/adjuvant ADT?
• Can outcomes be improved with docetaxel?
• Can outcomes be improved with immunotherapy?
• Is whole pelvic RT or ePLND more effective?
• Can staging be improved with new imaging techniques?
• What are the patient risk factors that affect oncological control and toxicity?
• How much of the improved survival is a delay due to cytoreduction, and how much is actual cure?

EBRT with 2 years of ADT better than 4 months in patients treated for locally advanced prostate cancer

It will come as no surprise that long-term ADT improved outcomes among men treated for locally advanced prostate cancer with external beam radiation. While this study is largely irrelevant now because a more recent study, DART 01/05 (discussed here), proved much the same thing with dose-escalation, this study also included pelvic lymph node treatment and has a median of 20 years of follow up.

The final results of RTOG 0902 were reported at the recent ASTRO meeting by Lawton et al. and in a news release. In this multi-institutional study, 1,992 patients were treated between 1992 and 1995. They were all high risk (T2c-T4) with no detectable distant metastases and PSA<150. All patients ere treated according to the following protocol:

• ·      44-46 Gy to the pelvic lymph nodes
• ·      65-70 Gy to the prostate
• ·      The short-term ADT group (STADT) received 4 months of flutamide and goserelin, starting 2 months before EBRT.
• ·      The long-term ADT group (LTADT) received 24 additional months of goserelin.

At 15 years after treatment:

• ·      Disease-free survival was 16% for the LTADT group vs. 10% for the STADT group, and was statistically significant.
• ·      PSA increase was 45% for the LTADT group vs. 61% for the STADT group, and was statistically significant.
• ·      Local progression was 13% for the LTADT group vs. 23% for the STADT group, and was statistically significant.
• ·      Distant metastases rate was 17% for the LTADT group vs. 26% for the STADT group, and was statistically significant.
• ·      Disease-specific survival was 10% higher for the LTADT group vs. the STADT group, and was statistically significant.
• ·      Overall survival was 30% for the LTADT group vs. 27% for the STADT group, and was not statistically significant.
• ·      No difference in urinary toxicity and minimal difference in bowel toxicity between the two groups.

While all the survival numbers are very low in both groups, it should be recalled that the radiation dose received back then was well below the dose now considered curative. Also, most of such men would now be diagnosed at a much earlier stage of disease progression. There was a clear benefit to long-term compared to short-term androgen suppression, and DART 01/05 proved that the benefit was still true with dose escalation in high-risk patients.

Adding ADT to radiation therapy may carry increased cardiovascular risk

Some recent randomized clinical trials have demonstrated that adding ADT to radiation therapy can improve outcomes in some circumstances. However, a new study from Memorial Sloan Kettering Cancer Center (MSKCC) suggests that its use may require caution in some patients.

Kohutek et al. retrospectively analyzed the records of 2,211 MSKCC patients treated with radiation therapy from 1998 to 2008. Almost half (45%) received adjuvant ADT with their radiation for a median of 6.1 months. Some of the men (17%) received salvage ADT after radiation failure. They found:

• ·      Incidence of cardiovascular events (CE) was significantly higher among men who received the adjuvant ADT (20%) compared to those who didn’t (14%).
• ·      The following risk factors were associated with CE: adjuvant ADT, salvage ADT, older age, smoking, diabetes, and previous history of CE. Those factors predict CE with 81% accuracy.

We should use a bit of caution in interpreting these findings. First, this was a retrospective analysis and not a randomized clinical trial, so it is entirely possible that the men selected to receive adjuvant ADT were also more prone to CE for other reasons. Also, CEs increase with age, but so does the incidence of more aggressive prostate cancer, so it is hard to separate cause and effect here. Finally, the increase in risk from 14% to 20%, while statistically significant, may not be clinically meaningful enough to forgo adjuvant treatment.

The New Prostate Cancer Infolink has recently reported on cardiovascular risk associated with ADT in the Swedish registry, and in the SEER database. Just as with those studies, this one does not constitute proof, but it does suggest caution until such time as a clear link is proven or disproven. In particular, we have no proof of oncological benefit of adding ADT to radiation treatment of favorable risk prostate cancer, or when the radiation is hypofractionated. Patients should be clearly apprised of the risk and be alert for early symptoms.

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.

ADT and radiation for first-line treatment of node-positive (N1) prostate cancer

It’s now a rare occurrence (12%) to be newly diagnosed with pelvic lymph node positive (N1) prostate cancer. Traditionally, this had been treated with ADT only because radiation therapy (RT) was thought to be of no benefit in extending survival. A new study seems to show that adding RT to ADT can extend survival.

There are a couple of reasons why this kind of diagnosis is rare. First, since PSA-screening became widespread in the US, patients are usually diagnosed before the cancer has spread to the lymph nodes (LNs). Secondly, while detection tools have improved, detection of positive nodes remains challenging. CT scans can only detect lymph nodes that have been seriously enlarged by cancer invasion, and enlargement doesn’t necessarily mean it’s cancerous. For that, a confirming biopsy is necessary yet very difficult because of huge anatomic variation and the near-invisibility of LNs. Multiparametric MRIs and C11-Choline PET/CT may improve diagnostic accuracy over CT alone, but they lack the sensitivity we would ideally want. There is hope that the new generation of PSMA antibody-linked PET-indicators, especially when tied to the new PET/MRI machines, may improve diagnostic accuracy. USPIO MRIs have been used to find cancerous LNs, but not in the first-line therapy setting. Cost of screening may be prohibitive for any of these to be used routinely.

Let’s distinguish between several settings in which radiation might be used on lymph nodes. All of these settings assume there are no distant metastases (M0):

a. First-line RT to the whole pelvis when cancerous nodes have been identified. I will be addressing setting “a” in this article.

b. First-line RT to the whole pelvis when cancerous nodes are suspected but not identified. This was the subject of the clinical trial RTOG 94-13, and the ongoing clinical trial RTOG 0924.

c. Adjuvant or salvage RT to the pelvic LNs when cancerous nodes have been identified. This was the subject of two retrospective studies published last year by Abdollah et al.  and by Rusthoven et al. that showed a benefit to salvage RT, and one by Kaplan et al. that showed no benefit. Update (10/2017) analyses by Zareba et al. of the National Cancer Database and by Touijer et al. of retrospective data from MSK, Mayo and San Raffaele Hospital (Milan) also suggest a benefit to salvage RT.

d. Adjuvant or salvage RT to the pelvic LNs when cancerous nodes are suspected but not identified. This is the subject of the ongoing clinical trial RTOG0534.

e. Spot radiation to one or several LNs upon recurrence after radical prostate treatment. This was the subject of some small studies by Picchio et al., Bonomo et al., and Jereczek-Fossa et al.

(Update 4/2019) Sargos et al. reported the results of a multi-institutional randomized trial comparing whole pelvic radiation+ADT to ADT alone in 263 men with locally advanced prostate cancer.

• all men received 3 years of Lupron
• half the men also received 66-74Gy to the prostate and 46 Gy to the whole pelvis
• 8-year progression-free survival was 48% for RT+ADT vs 7% for ADT alone
• 8-year prostate cancer mortality was reduced by 48% by adding RT
• 8-year overall survival was 65% for RT+ADT vs 57% for ADT alone (similar at 8 years)
• 8-year metastasis-free survival was similar at 8 years, but loco-regional progression was lower in the RT+ADT arm

In a 2001 study from MD Anderson, Zagars et al. retrospectively looked at patients who had a prostatectomy between 1984 and 1998, but where the surgery was not completed after positive LNs were detected. Traditionally, if frozen sections of pelvic nodes revealed cancer, the prostatectomy was discontinued and ADT only was immediately begun. Such patients fared much better in terms of disease progression if they were treated with both ADT and RT than if they were treated with ADT alone. After 10 years, the overall survival among those who received RT and ADT was 67%, but only 46% if they only received ADT.

In a 2013 retrospective analysis of the SEER database, Tward et al. found 1,100 patients who were diagnosed with node-positive prostate cancer between 1988 and 2006. The 10-year prostate cancer specific survival was 63% among those who received definitive RT, but was significantly lower, 50%, among those who did not.

In a similar analysis of the SEER database last year, Rusthoven et al. found 796 patients who were clinically diagnosed with positive lymph nodes between 1995 and 2005. 43% had RT and the rest had no local therapy. The 10-year prostate cancer specific survival was 67% if they received definitive RT, but was 53% if they did not.

In an early subgroup analysis of the STAMPEDE trial, those who were N1 and received ADT and RT (at least RT was planned) had a 2-year failure-free survival of 85%. This compared to only 55% among those who were N1 and received only ADT.

In an analysis of the National Cancer Database, Lin et al. identified 3,682 patients who were clinically diagnosed with positive lymph nodes between from 2004 to 2011. A third were treated with ADT only, and a half had both RT and ADT. The 5-year overall survival was 86% for those who received both RT and ADT, but was 71% if they received ADT only. They found 331 matched pairs of patients who had similar risk factors, and found that adding RT to ADT decreased 5-year mortality by 58%. The authors conclude:

"These data, if appropriately validated, suggest that a significant proportion of such patients at high risk for prostate cancer death may indeed be undertreated warranting a re-evaluation of current practice guidelines.”

Further evidence that whole-pelvic RT may be beneficial for all node-positive patients comes from retrospective analyses of its use in the salvage setting. As mentioned in setting “c” above, several previous studies have looked at adjuvant or salvage RT after positive lymph nodes have been detected during prostatectomy using  pelvic lymph node dissection (PLND). Extended PLND (ePLND) is gaining in popularity, especially in Europe, in which 30 or more pelvic lymph nodes are extracted in hope of a providing a cure without adding RT. Alternatively, the surgeon may remove the prostate, and refer the patient for adjuvant RT. While the two most recent retrospective studies have shown a survival benefit to adjuvant/salvage radiation, one did not, and we do not yet have a randomized clinical trial to provide definitive answers.

While most of these recent studies suggest a benefit to whole pelvic RT treatment of node positive newly diagnosed prostate cancer, we cannot be sure of that until randomized clinical trials are conducted. To my knowledge, there are none so far.

The other side of the equation is the effect of pelvic radiation on quality of life. The data are equivocal. In RTOG 94-13, Grade 3 lymphopenia, and Grade 3 GI toxicity was a problem for 8% and 5%, respectively,  among those receiving neoadjuvant ADT and whole pelvic RT.  DeVille et al. noted a higher rate of acute GI toxicity, but not late GI toxicity. At escalated doses, Johnson et al. noted that late term GI toxicity was much higher in men who received whole pelvic RT, while Patel et al. noted no significant difference in toxicity.

There are many outstanding questions, with few clear answers, for the doctor and patient to discuss with respect to RT for N1 prostate cancer:

• What is the most appropriate radiation dose?
• Is there a limit to the number of infected nodes beyond which it is fruitless to use RT? 
• Should simultaneous integrated boost RT be used on infected nodes? 
• Can SBRT equal or improve the risk/benefit profile over IMRT? 
• What is the best timing for neoadjuvant/concurrent/adjuvant ADT? 
• Can outcomes be improved with docetaxel? 
• Can outcomes be improved with immunotherapy? 
• Is whole pelvic RT or ePLND more effective? 
• Can staging be improved with new imaging techniques? 
• Can RT toxicity be reduced with improved image guidance or advanced delivery devices? 
• Should rectal spacers be used to reduce GI toxicity? 
• What are the patient risk factors that affect oncological control and toxicity? 
• How much of the improved survival is a delay due to cytoreduction, and how much is actual cure?

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.