Showing posts with label SRT. Show all posts
Showing posts with label SRT. Show all posts

Monday, November 28, 2016

Dose Escalation for Salvage Radiation

In the late 1990s and early 2000s, the advent of more accurate linear accelerators (linacs) and image-guidance technology for delivering therapeutic X-rays to prostate cancer changed the dose that could be safely given. In the late 1980s, the typical dose was only in the mid-60 Gy range. By the early 2000s most of the top prostate cancer treatment centers were delivering 80 Gy (at 1.8 or 2.0 Gy per treatment) with higher cure rates and lower toxicity. Dose escalation for primary treatment of prostate cancer was a resounding success and became the standard of care.

However, dose escalation was not utilized appreciably in salvage radiation treatment (SRT) after prostatectomy. The reasons doses were kept lower in the salvage setting were that:

  • Toxicity might be higher because radiation could be especially damaging when applied to tissue that had been cut or stressed by surgery.
  • Without the shielding effect of the prostate in place, sensitive structures like the bladder neck, the rectum, the penile bulb, and the urethra would receive the full brunt of the radiation.
  • Unlike the relatively large tumors in an intact prostate, the cancer in the prostate bed was small or microscopic and didn’t need as large a dose of radiation to eradicate it.

Current guidelines by the American Urological Association (AUA) and The American Society of Radiation Oncologists (ASTRO) establish a minimum dose of 64-65 Gy for SRT, but do not establish an optimum dose, citing lack of available evidence. At the top treatment centers, radiation oncologists routinely deliver doses as high as 70 Gy, but seldom higher. The outstanding question is: what is the optimum dose for SRT? That is, what dose offers the best chance at a cure with acceptable toxicity?

The Dose/Response Curve

Radiation oncologists talk about an S-shaped “dose/response curve.” At the bottom of the “S,” we know that at very low radiation doses there is very little “response,” meaning very few cancer cells are killed. At a certain radiation level, a lot more cancer cells are killed, and even a small increase in dose will kill a lot more cancer cells. This is called the “steep” part of the dose/response curve. After the steep part, adding more dose doesn’t kill a lot more cancer cells, but it begins to kill off healthy cells, increasing toxicity. The optimal dose is reached just before this happens at the top of the steep part. Below is what a dose/response curve looks like:

The Study

Dr. Christopher King (see this link) analyzed data from 71 studies, representing 10,034 patients treated who received SRT between 1996 to 2015 to see if the data conformed to a dose/response curve. He found an excellent fit:
  • SRT dose was the single most important factor correlated with recurrence-free survival
  • PSA at the time of SRT was the second most important factor
  • Other factors (stage, Gleason score, positive margins, lymph node invasion, and use of adjuvant ADT) were less important.
  • At an SRT dose of 66 Gy, half the patients were recurrence-free after SRT
  • Recurrence-free survival increased by 2 percentage points for each additional Gy of SRT dose.
  • The dose/response curve for SRT fit almost perfectly to the dose/response curve for primary RT.
Because the curves seem to be identical whether it was for primary therapy or for salvage therapy, it implies that even the microscopic prostate cancer cells lingering in the prostate bed require as much radiation to finish them off as the larger tumors within the prostate. This radioresistance will not surprise those of us who have noticed the improved cancer control patients get with a brachytherapy boost given for primary radiation therapy.

How much better cancer control can we expect?

It’s hard to know how high recurrence-free survival can get if the dose is increased. The statistics suggest that increasing the SRT dose from 66 Gy to 76 Gy will increase recurrence-free survival from 50% to 70% at 5 years of follow-up. But this is unknown territory, and in some patients, undetectable distant metastases will have already occurred. Of the 71 studies reviewed in this meta-analysis, only 4 included doses above 70 Gy. Dr. King is proposing a clinical trial where patients are randomized to receive 66 Gy or 76 Gy.

76 Gy for SRT – is that safe?

Only one study included a dose this high. Ost et al. treated 136 patients. 5-year biochemical recurrence-free survival was 56%, but patients were treated fairly late – median PSA had already reached 0.8 ng/ml by the time SRT began, and most had adverse pathology findings. They report reasonable late toxicity: 4 patients (3%) suffered a grade 3 urinary event, and 1 case of a grade 3 rectal adverse event. However, they do note that a lot of the grade 2 toxicity seemed to be chronic rather than transient. 39% suffered long-lasting grade 2 urinary toxicity, and 18% suffered from long-lasting grade 2 rectal toxicity. I assume patients will be excluded from Dr. King’s clinical trial if they still have urinary issues from surgery. There is no data on the effect of dose escalation on erectile dysfunction.

There has been one randomized clinical trial of SRT dose escalation in the modern era. The SAKK 09/10 trial found little difference in acute toxicity symptoms at 70 Gy compared to 64 Gy, but patient-reported urinary symptoms worsened.

Can SBRT be used instead of IMRT?

There have been a few clinical trials of hypofractionated SRT that seem promising (see this link). UCLA will be starting a trial next year as well. An IMRT dose of 76 Gy is biologically equivalent in its cancer control to 5 SBRT treatments totaling 33 Gy.

The challenges for SBRT are greater than for IMRT. Because the dose per treatment is so high, even a small “miss” can increase toxicity and reduce effectiveness. It is difficult to use fiducials in the prostate bed, and the soft tissue is highly deformable and subject to motion from the bowels and bladder. The radiation oncologist will have to use soft tissue landmarks and site them multiple times per treatment. A filled bladder and good bowel prep are important, as is a very fast linac. Careful planning and strict adherence to dose constraints to organs at risk are essential.

Implications for pelvic lymph node treatment

If prostate cancer in the prostate bed requires almost 80 Gy, what can we infer about microscopic cancer that has spread to pelvic lymph nodes? It would seem that that cancer would be equally radioresistant. The pelvic lymph nodes area is often treated with a dose of about 50 Gy. Unfortunately, as the radiation field increases to extend to the entire pelvic area, many more organs are subject to toxic reactions. The enteric tissue of the small bowel is particularly prone to late reactions. In a database analysis at Fox Chase Cancer Center, patients treated with 56 Gy to the whole pelvis for high-risk prostate cancer may have had gastrointestinal reactions as long as 9 years later. We await the findings of randomized clinical trials (RTOG 0534 and PRIAMOS1) to tell us whether such treatment is effective.

Discuss with your radiation oncologist

Although Dr. King’s meta-analysis is impressive in the amount of data represented, it is not a randomized trial that would change clinical standards on its own. Even so, it is certainly worth discussing with one’s radiation oncologist before committing to a treatment plan. There are many considerations for the patient  - especially his current status with regard to urinary and erectile function. For patients with few adverse pathology findings (e.g., long PSA doubling time, low Gleason score, no obvious capsular penetration), the risk of extra toxicity may not be worthwhile. It’s a judgment each patient must make for himself.

Note: Thanks to Dr. Christopher King for allowing me to see the full text of his study.

Tuesday, November 1, 2016

PORTOS: a gene signature that predicts salvage radiation success

Salvage radiation is curative in roughly half of all cases. There are many factors that contribute to an unfavorable prognosis, including waiting too long, high PSA and rapid PSA doubling time, adverse post-surgery pathology (stage, Gleason score, positive margins), and high Decipher or CAPRA-S score. But, other than a detected distant metastasis, none can predict failure of salvage therapy. For the first time, there seems to be a genetic signature that predicts when adjuvant or salvage radiation  (A/SRT) will succeed.

The study is all the more impressive because of the many top prostate cancer researchers attached to it, representing a collaborative effort from many top institutions: Harvard, University of Michigan, Johns Hopkins, Northwestern University, University of California San Francisco, Mayo Clinic and others.

The process

Zhao et al. started with data on 545 patients who had a prostatectomy at the Mayo Clinic between 1987 and 2001. They attempted to find patients who were matched on pre-RP PSA, Gleason score, stage, and positive margins, but differed on whether they received A/SRT or not. They also had to have complete information on diagnosis and whether they eventually had metastatic progression. This yielded 98 matched pairs. They then did complex genetic screening of archived tissue samples from those prostatectomy patients, focusing on 1800 genes that have been implicated in response to DNA damage after radiation. They found 24 genes that were correlated with occurrence of metastases after salvage radiation. After correcting for other factors, they determined what they call a “Post Operative Radiation Therapy Outcomes Score (PORTOS).” A PORTOS of zero (called a “low” PORTOS) means it predicts no benefit from salvage radiotherapy. A PORTOS greater than zero (called a “high” PORTOS) predicts a benefit from salvage radiation.


The next phase was to predict how well the 24-gene signature would predict salvage radiation success in a larger data set. They analyzed 840 patient records from patients treated at the Mayo Clinic from 2000-2006, Johns Hopkins (1992-2010), Thomas Jefferson University (1999-2009) and Durham VA Medical Center (1991-2010). They were able to find 165 matched pairs – half treated with A/SRT, half with no radiation. Tissue samples were screened and scored, and 10-year incidence of detected metastases was obtained. 1 in 4 men were categorized as “high PORTOS,” 3 in 4 were “low PORTOS.”

In the “high PORTOS” group: 
  • Only 4% suffered metastatic progression if they had A/SRT
  • 35% suffered metastatic progression if they did not have A/SRT
  • They had an 85% reduction in 10-year incidence of metastases after A/SRT, which was statistically significant.
In the “low PORTOS” group:
  • 32% suffered metastatic progression if they had A/SRT
  • 32% suffered metastatic progression if they did not have A/SRT
None of the other prognostic tools (Decipher, CAPRA-S, or Prolaris) that are sometimes used to predict metastases after prostatectomy could predict the response to A/SRT.


This should be interpreted with caution for several reasons:

It was retrospective, and therefore subject to selection bias. That is, the physicians may have decided on the basis of patient characteristics or other disease characteristics not captured here to give A/SRT to some patients, but not to others. Only a prospective, randomized trial can tell us if the association with PORTOS is the cause of the differential response.

Among the disease characteristics the researchers were unable to capture for this study were the time between prostatectomy and A/SRT, PSA at time of A/SRT/maximum PSA reached, nadir PSA achieved after prostatectomy, PSA doubling time, extent of positive margins, Gleason score at the positive margin, and comorbidities. Patients were not treated uniformly with respect to radiation dose received and duration of adjuvant androgen deprivation therapy (ADT). Only 12% received any adjuvant ADT, and only 12% received adjuvant (rather than salvage) radiation.

Metastases were detected by bone scan and CT. Lymph node dissection, if performed, was limited. It was detected in 4% of the “low PORTOS” group, but in none of the “high PORTOS” group. It is unclear how today’s newer PET scans would affect outcomes.


Prostate cancer has long been known to be radioresistant relative to other cancers. To understand radioresistance, we must first understand how ionizing radiation (X-rays or protons) kills cancer cells. The radiation causes a chemical reaction with water and oxygen to generate molecules known as “reactive oxygen species” or ROS. One such ROS molecule, the hydroxyl radical, inserts itself into the cell’s DNA to break both strands of the double helix, called “double strand breaks.” The cell dies when it can’t replicate because of those double strand breaks.

Radiobiologists cite 5 reasons for radioresistance:

1. Hypoxia

Prostate cancer thrives in an oxygen-poor environment, and often does not have a good blood supply that brings oxygenation. It therefore requires more radiation to provide adequate ROS, especially into thick tumors.

2. Cell-Cycle Phase

As a cancer cell attempts to build new DNA and replicate, it goes through several phases. In one of those phases, the “S phase,” the cell is building new DNA. It is particularly radioresistant in this phase. Radiotherapy is typically carried out over a period of time in multiple fractions, rather than in a single shot, to allow the cancer cells to cycle into more radiosensitive phases. However, in a recent lab study, McDermott et al. showed that fractionated radiation increases the population of radioresistant S-phase prostate cancer cells.

3. Repair of DNA damage

Non-cancerous cells that can’t repair the DNA damage, commit suicide (called apoptosis). Many non-cancerous cells are able to repair the DNA damage and survive. Fractionation gives them time to self-repair. Cancerous cells usually lack that DNA-repair mechanism and most cannot undergo apoptosis. If they are not killed immediately, they die when they try to replicate. However, some cancerous cells may escape destruction by turning the genetic cell repair mechanism back on.

4. Repopulation

Some cancers grow so quickly that fractionated radiation gives them time to grow back between treatments. This is not the case for prostate cancer.

5. Inherent radioresistance

Some kinds of cells are inherently impervious to radiation damage; muscle, nerves, and stem cells are radioresistant, as are melanoma and sarcoma. Prostate cancer stem cells, thought to play a role in prostate cancer proliferation, are inherently radioresistant. A recent lab study showed that radiation may paradoxically activate stem-cell like features of prostate cancer cells, turning them into radioresistant stem cells.

How should PORTOS be used?

GenomeDx is already supplying PORTOS to post-prostatectomy patients who order Decipher. Should it be used to guide A/SRT decision-making? Given the caveats (above), there are many uncertainties in how predictive it actually will be when it is used prospectively in larger patient populations. But the information is certainly interesting.

I wonder whether PORTOS reflects a genetic change that occurs in local prostatic cancer cells as they undergo a change (called “epithelial-to-mesenchymal transition” (EMT)) into metastatic-capable cells. Or is it a genetic characteristic, there from the start? A recent study showed that 12% of men with metastases have faulty DNA-repair genes. (This included 16 DNA-repair genes, compared to the 24 in the PORTOS study). Such faults occurred in 5% of men with localized prostate cancer, and 3% in men with no prostate cancer. DNA-repair mutations seem to accumulate as the cancer progresses. It may well be that PORTOS is an early detector of systemic micrometastases. Perhaps it will be found to be redundant to detection of small metastases using new PET indicators. I would love to see a PORTOS analysis on metastatic tissue as well (lymph node, bone and visceral) and maybe on circulating tumor cells to see whether radioresistance is an acquired trait of PC progression. If it is an early indicator of metastatic progression, it may already be too late for primary radical therapy.

While a “high” PORTOS suggests that A/SRT will be curative, only a quarter of the men had a high PORTOS. Does that really mean that three-quarters of recurrent men should give up on curative therapy? If PORTOS is not an indicator of EMT, I hope that those recurrent cancers still can be cured. But it may mean that certain adjuvant measures may be required, including higher radiation doses, systemic therapies that are known to enhance radiation effectiveness, and investigational adjuvant therapies.

      A/SRT doses are typically in the range of 66-70 Gy. Some A/SRT studies used doses as high as 72-76 Gy. With modern IGRT/IMRT technology, such doses may be delivered with acceptable toxicity. Also, if larger lesions can be identified with the new PET scans and multiparametric MRIs, it may be possible to deliver a simultaneous integrated boost dose to those lesions.

      ADT has been shown to reduce hypoxic cancer survival and inhibit DNA repair. It is possible that prolonged neoadjuvant use, perhaps with second-line hormonal agents (Zytiga or Xtandi) may improve radiation cell kill. Docetaxel, which has shown limited usefulness in non-metastatic patients, may prove useful in low-PORTOS situations. Perhaps immunotherapy can play a role as well.

    There are many investigational agents that may enhance radiosensitization. PARP1 inhibitors (e.g., olaparib) and heat shock protein inhibitors may prove useful in restoring radiation sensitivity (see this link). PI3K/mTor inhibitors and HDAC inhibitors (e.g., vorinostat) may increase cell kill in hypoxic conditions (see this link) and to cancer stem cells (see this link). Cell oxygenation may be enhanced by a measure as simple as 15 minutes of aerobic exercise before each treatment (see this link). There are common supplements like resveratrol and soy isoflavones, and drugs like statins, aspirin, and metformin that have shown promise as radiosensitizers in lab studies.

It is possible that PORTOS may also prove useful in predicting radiation response among newly diagnosed unfavorable risk patients. GenomeDx  currently requires whole-mount prostate specimens. I don’t know if PORTOS can be done on biopsy cores, or if it provides any prognostic information beyond what the conventional risk factors (PSA, Gleason score, stage and tumor volume) provide. It would have to be similarly validated before we would be able to incorporate it in primary therapy decision-making.

This test is very expensive. For now it only is available along with Decipher, which costs about $4,000. Medicare may cover it, but private insurance may or may not. Always get pre-authorization first.

Monday, October 3, 2016

Urinary and sexual healing improved by waiting to start salvage radiation

Salvage radiation adds to the side effects of surgery and may halt the progress made towards healing. Healing takes time. On the other hand, we have learned that adjuvant or early salvage radiation has better oncological outcomes than waiting, the earlier the better (see this link).  Two new studies help us better understand the trade-offs.

Zaffuto et al. examined the records of 2,190 patients who had been treated with a prostatectomy. Their urinary and sexual outcomes were evaluated based on whether they received:
  1. no radiation
  2. adjuvant radiation (prior to evidence of recurrence, usually administered 4-6 months following prostatectomy), or
  3. salvage prostatectomy (after PSA reached 0.2 ng/ml)

They also looked at outcomes based on when they were treated with radiation:
  1. Less than a year after surgery, or
  2. A year or more after surgery

With median follow-up of 48 months, the 3-year outcomes were as follows.

Erectile function recovery rates were:
  • 35.0% among those who received no radiation
  • 29.0% among those who waited to receive salvage radiation
  • 11.6% among those who had adjuvant radiation
  • 34.7% among those who waited for a year or more before initiating salvage radiation
  • 11.7% among those who had radiation within a year

Urinary continence recovery rates were:
  • 70.7% among those who received no radiation
  • 59.0% among those who waited to receive salvage radiation
  • 42.2% among those who had adjuvant radiation
  • 62.7% among those who waited for a year or more before initiating salvage radiation
  • 43.5% among those who had radiation within a year

Van Stam et al. looked at their database of 241 patients who were treated with salvage radiation and 1005 patients who only received a prostatectomy but no radiation afterwards. All patients were last treated between 2004 and 2015, and had up to 2 years of follow-up afterwards.

After adjusting for patient characteristics, they found that:
  • Salvage radiation patients had significantly worse recovery of urinary, bowel, and erectile function.
  • Patients who waited more than 7 months before receiving salvage radiation had better sexual satisfaction scores and better urinary function recovery.

So what is one to do: treat earlier for better odds of cancer control, or treat later for better urinary and sexual function recovery? We have seen that adjuvant radiation is rarely likely to be necessary, and that early salvage radiation can probably be just as effective. But what if PSA is already high and rising rapidly? One solution might be to use hormone therapy to halt the cancer progression while tissues heal. That may help with urinary function, but is apt to interfere with recovery of sexual function. This remains a difficult decision, which is why discussions with an experienced radiation oncologist should begin at the earliest detectable PSA (over 0.03 ng/ml) on an ultrasensitive test. Most of all, the patient must do the self-analysis to understand which trade-offs he is willing to make.

Tuesday, August 30, 2016

Metastases after early vs. delayed salvage radiation

Until we have the results of randomized clinical trials on the relative efficacy of early salvage radiation, we have to look for other clues to inform the timing of that decision. Adjuvant radiation carries a high risk of overtreatment, whereas delayed salvage may preclude the window of opportunity during which salvage radiation might have been curative.

Den et al. posted the outcomes of their investigative analysis at the ASCO Genitourinary Conference (Abstract 12). Data on 422 patients treated at 4 institutions were retrospectively analyzed. All had adverse pathology (either stage T3 or positive margins) after RP. Patients were arbitrarily divided according to their PSA after surgery at the time they received radiation:
  • ·      <0.2 ng/ml – “adjuvant RT” (111 patients)
  • ·      >0.2 but <0.5 ng/ml – “early salvage RT” (70 patients)
  • ·      >0.5 ng/ml – “delayed salvage RT” (83 patients)
  • ·      No radiation received (157 patients)
CAPRA-S scores and Decipher genomic classifier scores were found to independently predict risk of metastatic progression. Adjusting for those scores:
  • ·      Delayed salvage RT increased risk of metastases by 4.3 times over adjuvant RT
  • ·      No radiation increased risk of metastases by 5.4 times over adjuvant RT
  • ·      Early salvage and adjuvant RT had about the same risk of metastases
  • ·      Men with low CAPRA-S and Decipher scores had low risk of metastases
  • ·      Men with high CAPRA-S and Decipher scores benefit from adjuvant RT, but had high rates of metastases nonetheless.

This study once again underscores the importance of early salvage radiation for curative therapy after failed surgery when there is adverse pathology. They didn’t investigate the use of ultrasensitive PSA to determine what the lowest level that avoids overtreatment might be. Adverse pathology and PSA are important to consider, but other clinical/genomic factors can contribute to the decision-making process as well. Low Decipher scores can help rule out those cancers that are unlikely to metastasize in the next 5-10 years. However, it is less useful at indicating those cancers that will metastasize.  And there are no good tests for determining if the cancer is already systemic and micrometastatic, in which case salvage radiation would be futile. This remains a challenging situation for discussion between the patient and radiation oncologist.

Monday, August 29, 2016

Antiandrogen therapy enhances outcomes of salvage radiation

Two years of antiandrogen therapy improved survival in patients treated with salvage radiation. This report represents an update with over 12 years of median follow up. The results with 7 years of follow-up were previously reported here.

The results of the randomized clinical trial RTOG 96-01 were presented by Shipley et al. at the recent ASTRO meeting and reported in a press release. Between 1998 and 2003, 761 patients were treated at multiple sites across the US and Canada. All patients had biochemical recurrence and either stage pT2 with a positive margin or stage pT3, without lymph node involvement or metastases. All patients received 64.6 Gy of EBRT in 1.8 Gy increments (36 fractions), and either 24 months of bicalutamide (150 mg) or a placebo. After 12.6 years median follow up, the antiandrogen had the following effects:
  • ·      Reduced tumor progression and the incidence of local re-growth
  • ·      Reduced rate of metastases from 23% to 14%
  • ·      Reduced death from PC from 7.5% to 2.3%
  • ·      Improved overall survival at 10 years from 78% to 82% (p=.04)
  • ·      GI or GU toxicity were low and similar in both arms.
  • ·      Gynecomastia was common with bicalutamide.

While the salvage radiation dose delivered in this study falls short of the 70 Gy now considered adequate, it does provide evidence of a survival benefit linked to added hormone therapy. Another randomized clinical trial, GETUG AFU-16, proved that even a short course of ADT significantly improved progression free survival when used with salvage radiation, but longer follow up will be necessary to prove a benefit in prostate cancer survival. RTOG 96-01 proves that prostate cancer specific survival is indeed improved by the combination of hormone therapy with salvage radiation, although the benefit may be limited to those with lower PSA and negative margins.

Sunday, August 28, 2016

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).

    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% 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.