New Study: Adjuvant Radiation Saves Lives vs. Salvage

A major new study adds to several other studies that show that, for men with adverse pathology, adjuvant radiation (ART) within 3-6 months of prostatectomy saves more lives compared to waiting until the PSA rises into the range of 0.1-0.5 ng/ml - salvage radiation (SRT).

Three previous randomized clinical trials have shown an advantage to adjuvant radiation over a "wait-and-see" approach. However, only one of them (SWOG  S8794) showed that there was an improvement in freedom from metastases and overall survival attributable to earlier treatment. That study was limited in its generalizability because only a third of the "wait-and-see" cohort ever received salvage radiation. ARO-96-02 was designed to detect differences in progression-free survival (which were significant), but it was underpowered to detect overall survival differences. EORTC 22911 was designed to detect differences in progression-free survival (which were significant), but although it had a larger sample size, overall survival did not improve. Sub-group analysis showed the survival benefit was limited to men under the age of 70. A recent meta-analysis of the three trials showed that freedom from biochemical failure, freedom from life-long ADT,  and freedom from distant metastases were significantly improved by adjuvant treatment. But less than half of the men in the wait-and-see arms ever received salvage radiation, and 20-40% of  them never suffered a recurrence. All three trials used salvage radiation doses that would now be deemed too low. ART utilization rates are at an all-time low of 17% in men with adverse pathology.

What we really want to know is: what is the downside of waiting until the PSA rises to some arbitrary level, say 0.2 ng/ml? That is the subject of three randomized clinical trials, but we will not have the findings for several years. Meanwhile, some researchers looked at historical data in a new way to determine whether there is any evidence that might aid in decision-making.

Hwang et al. have pooled the databases from ten top institutions: Massachusetts General, Cleveland Clinic, University of Michigan, Duke University, Washington University, Mayo Clinic, University of Chicago, University of Miami, Virginia Commonwealth University, and Thomas Jefferson University. There were 1,566 patients who were treated between 1987-2013. Patients either had fully contained prostate cancer (T2) with a positive margin or extraprostatic extension (T3a)/ seminal vesicle invasion (T3b) with or without a positive margin.

They used a statistical technique called "propensity score matching" that in some respects resembles what would have resulted from a prospective randomized trial. Every patient who had ART was matched, in terms of patient characteristics, to a patient who had SRT. Patients are chosen randomly from among those with matched characteristics.  Patients were matched on age at surgery, year of surgery, Gleason score, T stage, margin status, postoperative ADT, and pelvic nodal RT. In this way, they were able to generate 366 matched pairs of patients. This technique works quite well in predicting outcomes of prospective randomized trials as long as there is a large enough sample size, considerable overlap in patient characteristics (which there was) and there aren't any prognostic patient characteristics that were missed.

The researchers found that all measured outcomes were significantly better among those who received ART:

• 12-year freedom from biochemical failure: 69% for ART vs. 43% for SRT
• 12-year freedom from distant metastases: 95% for ART vs. 85% for SRT
• 12-year overall survival: 91% for ART vs. 79% for SRT
• Patients who suffered biochemical failure were more likely to have had SRT, have been stage T3b, have had higher Gleason score, had not been treated with lymph node radiation, and had not had postoperative ADT.
• The advantage of ART was only lost if more than 56% of them would have been overtreated, but based on nomograms, no more than 46% would have been overtreated (using the assumption that 2/3 were GS 3+4 and 1/3 was GS 4+3).

Pending confirmation by the randomized clinical trials, this study is our best evidence to date that ART is preferable to SRT. However, there are a few very important caveats:

• They defined SRT as treatment when the PSA is in the range of 0.1 - 0.5 ng/ml. (They actually call this "early" salvage -- a term I would prefer to reserve for radiation when the ultrasensitive PSA (uPSA) is below 0.10 ng/ml.) For uniformity reasons in this 10-institution study, any PSA below 0.10 ng/ml on an uPSA test was deemed "undetectable," and those treated at very low PSAs were considered to have had ART. They had to use those definitions in their analysis because of the heterogeneous data set with PSAs recorded as early as 1987 (before there were any ultrasensitive PSAs). Because the risk of overtreatment with ART is high (they estimate 33%-52%), it behooves patients to track their post-prostatectomy PSA with an ultrasensitive test. We have seen that for men with adverse pathology,  any uPSA over 0.03 ng/ml reliably predicts that it will keep going up to 0.2 ng/ml (see this link). In men without adverse pathology, only a convincing pattern of PSA rises is prognostic.
• Adverse pathology in this study included anyone with positive margins, but others advocate that the length of the positive margin and the Gleason score at the margin are important considerations. A patient with focal positive margins and GS 6 at the margin may never need additional ART or SRT.
• They lumped together men whose PSA was undetectable but then climbed higher and men whose PSA was persistently elevated after prostatectomy. Persistent PSA with adverse pathology is a clearer indicator that gross amounts of cancer were left behind and calls for some quick action.
• The Decipher genomic test was not available throughout most of the study period. For those sitting on the fence, it may be a decisive factor.
• The newer PET scans (Axumin and PSMA-based) can find metastases if PSA is greater than 0.2 ng/ml. Multiparametric MRI may be able to find sites in the prostate bed or among the pelvic lymph nodes where tumor size is longer than 4 mm. Because of the advantage of earlier treatment, most men will require treatment before metastases become detectable. Some will be overtreated if the cancer is already systemic.
• Among very high risk patients (i.e., GS 8-10, seminal vesicle invasion (T3b) or invasion of nearby organs (T4), and very high persistent PSA) the probability that ART or SRT will be curative may be very low. Patients should understand what the population-based risk is from a nomogram.
• The radiation doses delivered were at a median dose of 66 Gy. More recent evidence suggests that higher doses may be necessary to achieve a cure. The value of adjuvant ADT and whole pelvic radiation suggested here has also been suggested by a number of other studies.
• This study excluded patients with detected positive lymph nodes. That is a clear indication for ART.

There are many factors to consider including comorbidities, continence and potency recovery. This will seldom be a straightforward decision. Patients with adverse pathology and uPSA over 0.03 ng/ml should be talking to a radiation oncologist and not a urologist.

Hyperthermia and Radiation

Many years ago, it was discovered that a moderate increase in tissue temperature can markedly improve the cancer cell killing power of ionizing radiation. The temperature increase needed is not extreme. It is only necessary to increase temperature from 37°C (98.6°F) to something in the range of 41-43°C (106-109°F), which is the just a little warmer than a hot shower. Like a hot shower, it brings more blood into the warmed tissues, which may be the reason for its benefit.

The Theory

Blood flows to warm tissue in an effort to carry away the excess heat. Skin and muscle can easily tolerate temperatures of 44-46°C for an hour or more in a limited volume. But cancerous tissue does not have a good blood supply, so the heat accumulates preferentially there and cripples those cells. Those cancer cells are more susceptible to killing by radiation (or chemotherapy). The increased blood flow also increases the oxygenation that is necessary for radiation to work,  while protecting healthy cells. There is also be a direct cancer cell killing effect attributable to protein denaturation and inhibition of DNA repair. By denaturing the proteins that activate DNA repair, the cancer cells undergo "mitotic catastrophe" when they try to replicate. Sublethal radiation damage becomes lethal. At the same time, cancer cells are directly destroyed via several other mechanisms: senescence, apoptosis, and necrosis.

When subjected to heat stress, cells, whether cancerous or healthy, release protective heat shock proteins (HSP) both inside the cell and into the extracellular space. HSP is responsible for thermal resistance, which is why hyperthermia is not used at every radiation sessions in most studies. (Negating the protective effect using HSP inhibitors is an active area of oncological research.) In the studies below, hyperthermia was given only a few times during the course of an extended radiation schedule. On the other hand, HSP in the extracellular space chaperones cancer antigens to the immune system. Much of the benefit is thought to arise from a bystander or abscopal effect.

Hyperthermia would ideally be delivered at the same time as radiation (see the brachytherapy study below). But it can also be delivered up to 3 hours before radiation. It has also been used within a short time after radiation because it renders lethal what would otherwise be sublethal damage, and because of immune stimulation.

Not all types of cancer cells are vulnerable to hyperthermia. In a lab study, it was shown that prostate cancer cells were sensitive to hyperthermia (and hypothermia). A mathematical model showed that raising the tumor temperature to 42°C and delivering 76 Gy of radiation would be equivalent in cancer killing to raising the radiation dose to 86 Gy - effectively adding 10 Gy of cancer-killing power without increasing toxicity.

While it's important to have a theoretical framework showing why it should be beneficial, it is more important to demonstrate that benefit in clinical practice. There are four situations in which combining hyperthermia and radiation may be useful in  prostate cancer treatment: (1) Primary prostate treatment, (2) Salvage prostate bed treatment, (3) whole pelvic treatment, and (4) Palliative treatment of metastases.

Primary Prostate Treatment

Many of the studies on hyperthermia + radiation occurred in the 1990s when radiation doses were usually inadequate for cure, and there have been no randomized studies. The few studies tell us more about treatment-related toxicity than efficacy.

Hurwitz et al.  used just two transrectal ultrasound hyperthermia treatments before radiation on 37 locally-advanced patients who also received 66 Gy of radiation and 6 months of ADT. They found that heating the rectal wall to 42°C for about an hour was tolerable, and they allowed the interior temperature probe to go up to 43°C for 10 minutes. Toxicity was mild, with no patients suffering from serious (Grade 3) urinary or rectal toxicity. There was no relation between late-term rectal toxicity and rectal wall temperature. There was a relationship with acute rectal toxicity, although there was no toxicity greater than grade 2 (see this link). The same authors also found that perfusion of blood into the prostate increased most among those with the most hypoxic prostate tumors.

With longer follow-up, Hurwitz et al. reported that two-year recurrence-free survival was 84% with hyperthermia compared to only 64% in historical controls without hyperthermia. 7-year recurrence-free survival was 61% with hyperthermia (they didn't have a comparable 7-year historical control). The authors noted a relation existed between the maximum heating achieved in a patient and his recurrence-free survival.

Maluta et al. reported on 144 patients with locally advanced prostate cancer treated with 74 Gy of conformal external beam radiation, with ADT used short term in more than 60% of those patients. Hyperthermic therapy was given once a week for the first four weeks of EBRT. They noted no significant side effects, other than those associated with ADT and radiation. There was no toxicity greater than grade 2.

Kukielka et al. reported on 73 prostate cancer patients  (54 primary therapy for low- and intermediate-risk, 19 locally recurrent after primary EBRT) treated with hyperthermia + high dose rate brachytherapy. They found no complications other than those normally associated with brachytherapy. There was no toxicity above grade 2.

It has been proposed that tumors within the prostate, identified with mpMRI or PET scan, can receive a hyperthermia boost prior to radiation. Tis may prove useful in overcoming hypoxia.

Salvage Prostate Treatment

Kukielka et al. separately reported on 25 locally radio-recurrent patients treated with hyperthermia + high dose rate brachytherapy. The brachytherapy dose was 30 Gy in 3 fractions, and hyperthermia was applied before each fraction. There were no complications higher than grade 2. Two-year biochemical control was 74%.

There is an ongoing trial in Europe of hyperthermia in patients receiving salvage radiation (70 Gy) using 41°C for 60 minutes in the prostate fossa.

With Dr. King's analysis that suggests that current post-prostatectomy salvage radiation doses (of about 70 Gy) are inadequate, there may be a unique opportunity to raise the biologically effective dose without increasing radiation toxicity.

Whole Pelvic Treatment

In 2005, Tilly et al. reported on 22 patients who received regional hyperthermia along with 68.4 Gy of radiation for locally advanced or recurrent prostate cancer. None had positive lymph nodes. Acute toxicity was high, while late toxicity was mild. Thermal parameters were not correlated with toxicity, but higher temperatures were associated with better PSA control.

This reflects an underexplored opportunity in both primary and salvage treatment, and especially when cancerous lymph nodes have been detected by pelvic lymph node dissection (PLND) or imaging. Because of toxicity considerations, the pelvic lymph node area is only treated with about 50 Gy of conventionally fractionated radiation, which may be inadequate to kill all traces of the relatively radioresistant cancer. Hyperthermia may be able to boost the effective cancer-killing dose. In addition, it can be used less broadly to radiosensitize any specific positive lymph nodes that have already been identified.

Metastasis-directed Treatment

Chi et al. reported the first clinical trial where 57 patients were randomized to receive hyperthermia along with their radiation (30 Gy in 10 fractions) of painful bone metastases. Those who received hyperthermia, received it within 2 hours after radiation treatments twice weekly for 2 weeks. Their hyperthermia system used radiowaves (RF) to heat the metastases to the target temperature for 40 minutes. Pain palliation was the goal. The trial was ended early because the adjuvant hyperthermia was clearly superior. Complete pain palliation after 3 months was achieved in 59% of those who received hyperthermia, but only 32% of those who received radiation alone. Among those who had a complete pain response, median time to return of pain was 55 days among those who received radiation alone, but was not reached in the 24 weeks of follow-up among those who received hyperthermia.

Hyperthermia Technologies

Historically, technology kept hyperthermia therapy from gaining wide acceptance. Patients often suffered burns.The hyperthermia did not penetrate deep enough, and could not be accurately maintained. There were no guidelines for its use, and it was labor intensive to closely monitor each treatment. With low-toxicity radiation dose-escalation achieved with IGRT/IMRT, there was less need for the adjuvant thermal treatment. There are several technologies used to achieve hyperthermic temperatures. Hurwitz et al. used transrectal ultrasound with multiple temperature probes. Kukielka used RF implants directly into the prostate done at the same time as the brachytherapy implants. Others have investigated implanted ferromagnetic seeds that heat up when exposed to an alternating magnetic field. Chi et al. used RF at the surface to warm metastases.

Temperature inside the body can now be monitored from measurements taken from the surface, rather than internal temperature probes. Hyperthermia is prescribed in terms of cumulative equivalent minutes at 43°C achieved in 90% of the target area (CEM43T90). For each °C above 43°C, the time required for an equivalent effect is halved; for each °C below 43°C, the time required for an equivalent effect is fourfold higher. Typical CEM43T90 is at least 10 minutes. It is difficult to maintain the hyperthermic temperature because blood flow is continuously trying to carry away the excess heat. The patient typically spends about an hour on the table.

The problem with RF and MW energy is that much of their energy is deposited at the skin, causing burns. Microwaves do not penetrate deeply but can pinpoint a small area. RF can go deeper, but can only be used in wider areas. Ultrasound (US) is the technological breakthrough that enabled hyperthermia to treat deeper and wider areas, and it allows for greater accuracy. Low frequency US can penetrate deeply. Multiple US beams can be made to converge at the target tissue without overheating adjacent tissue. The only drawbacks of US are that it is strongly absorbed by bone, and it is interrupted and reflected by air pockets. This means that the spine and bones of pelvis must be avoided. It can also not be used across the rectum, unless the rectum is filled with a water balloon.

Treating the pelvic lymph node area may be problematic. It is large area deep within the body which may be difficult to heat and keep heated for a therapeutic length of time. Also, pelvic bones must be avoided.

Many hyperthermia clinics use the Sonotherm 1000. Its US can penetrate up to depths of 8 cm, which should be adequate to reach the entire prostate, and prostate bed. Similar to a multileaf collimator and intensity modulation used in radiation, it has an array of US transducers that can shape and focus the beams.

Research Directions and Treatment Centers

Because radiation technology has progressed so rapidly, it is now usually possible to curatively treat most patients with dose-escalated radiation without dose-limiting toxicity. Still, there may be instances where gross tumors have been identified within the prostate. Those tumors may exhibit a relatively radioresistant Gleason pattern 5, or they may have poor blood flow. There are opportunities for using hyperthermia to increase the biologically effective dose in the post-primary radiation and post-prostatectomy salvage situation and, if the technology can be worked out, to the whole pelvic region where radiation doses have historically been held low to avoid toxicity. Adjuvant hyperthermia for metastasis-directed therapy for pain palliation looks like a very promising use.

Although adjuvant hyperthermia is more popular in Europe, there are several centers in the US that are using it, notably UCSF, Washington University, Cleveland Clinic,  Dana-Farber,  Duke, and Thomas Jefferson University. One private clinic I spoke with suggests daily treatments, for which there is  no substantiation, may render the therapy less effective, and seems to be a money-grabbing ploy.

It seems that the technology has improved to the point that randomized clinical trials should be instituted. There seem to be only two clinical trials currently running in the US. Mark Hurwitz at Thomas Jefferson University is lead investigator on a trial using salvage high dose rate brachytherapy with interstitial hyperthermia in patients who are recurrent after radiation. Joe Hsu at UCSF is running a similar trial that is no longer open to recruitment.

Adjuvant hyperthermia is now Medicare-approved. If not covered by Medicare or insurance, patients may pay about $900 per treatment.

Thanks to BJ Choi at The Center for Thermal Oncology for explaining their protocol.

Salvage SBRT after Prostatectomy

UCLA has announced a new clinical trial using SBRT for treating recurrent prostate cancer after failure of initial prostatectomy. This is the third such trial in the LA area, adding to the ones at USC and  City of Hope (no longer recruiting). The advantages to the patient are completing salvage radiation in just 5 treatments, and at a lower cost. But there are many issues that the lead investigators, Amar Kishan and Chris King, explored in a very detailed document that they kindly allowed me to see. The hope is that the increased biologically effective dose possible with extreme fractionation will increase cure rates without adding undue toxicity.

Eligibility

Patients are eligible if they had adverse pathological findings (i.e., Stage T3/4, positive margins, Gleason score 8-10, tertiary pattern 5), or PSA rising over 0.03 ng/ml. They are excluding anyone who exhibits distant metastases on a bone scan (M1) or positive pelvic lymph nodes discovered by dissection (pN1). They are allowing patients with non-surgical evidence of pelvic lymph node invasion (i.e., suspected because of a CT or a PET/CT).

Radiation Dose / adjuvant ADT

The treatment plan is:

• All patients will receive 34 Gy in 5 fractions to the prostate bed. 
• There may be a simultaneous boost dose of 40 Gy to any detected tumors in the prostate bed.  
• Optionally, they will also receive 25 Gy in 5 fractions to the pelvic lymph nodes. 
• Optionally, they will also receive 6 months of ADT beginning 2 months before radiation begins. 

While whole pelvic radiation and adjuvant ADT improve salvage radiation outcomes on the whole (see this link), they may not be necessary in all cases. A recent analysis suggested that adjuvant ADT only benefits those with post-prostatectomy PSA ≥ 0.4 ng/ml, Gleason score 8-10, Stage T3b/4, and those with high Decipher scores (> 1 in 3 probability of distant metastases in 10 years).

The prostate bed dose is biologically equivalent to 85 Gy using conventional fractionation (about 1.8 Gy per fraction). It is much higher than the typical salvage radiation dose of 67 Gy - 72 Gy in 37-40 fractions. It also exceeds by about 9% the dose used in a trial of moderate hypofractionation (discussed here). At the last ASTRO meeting, Dr. King presented the rationale for increasing the salvage radiation dose (see this link).  At the time, he proposed a randomized clinical trial using a dose of 76 Gy with conventional fractionation. The new protocol far exceeds that dose on the basis of biologically effectiveness, but they will compare outcomes to historical controls. The goal is to achieve a 5-year biochemical recurrence-free survival rate of 72%, compared to the historical level of 56%.

Toxicity

Salvage SBRT isn't just another form of salvage IMRT; IMRT is more forgiving. With IMRT, if there is a small misalignment, it is not a big deal -- the dose per fraction is small enough that a target miss caused by organ motion will not materially affect outcomes and will average out over time.

• Only devices that continuously track prostate bed motion during, and not just at the start of, each treatment, and that operate with extremely fast treatment times may be able to avoid all of the geographic misses. Image guidance is complicated when there is nothing for fiducials to grab onto.  This becomes an important consideration only at higher dose rates.
• Although the biologically effective dose (BED) for oncological control is higher with the SBRT protocol, the BED to healthy tissues (which causes toxicity) is lower. 
• For the tissues that may cause acute toxicity, the BED is a third lower compared to a 72 Gy conventionally-fractionated treatment. In a recent trial of 70 Gy salvage radiation, acute grade 2 and 3 urinary toxicity was 18%; acute grade 2 and 3 rectal toxicity was 18% as well.
• For the tissues that may cause late-term toxicity, the BED is about the same. Serious late-term toxicity was a rare event when 76 Gy was used for salvage in one study, but late term grade 2 toxicity was about 20% urinary toxicity and 8% for rectal toxicity. It is unknown whether the late-responding tissues of the bowels and urinary tract will suffer increased damage from the higher dose rates after longer follow-up.

SBRT as a primary treatment is different from SBRT as a salvage treatment.  There are also several considerations that arise more in the salvage radiation therapy setting than in the primary therapy setting:

• The bladder and rectum are no longer shielded by an intact prostate, so they are potentially exposed to greater spillover radiation. The prostate bed without the prostate is highly deformable, and rectal distension can change its shape markedly within seconds during the treatment. This increases the amount of toxic radiation absorbed by healthy tissues.
• The scar tissue of the anastomosis may become inflamed, leading to a higher risk of urinary retention or tissue destruction.
• The bladder neck, which may be spared during primary radiation and surgery, receives a full dose during salvage radiation therapy, increasing the probability of bladder neck contracture, urethral strictures, pain and incontinence. These problems may be amplified at higher doses per treatment.
• Erectile function is probably already impaired from the surgery. Neurovascular bundles, if spared by surgery, are far more exposed during salvage radiation.

We have had a couple of cautionary cases where SBRT toxicity has been extraordinarily high. In one, it was because the delivered radiation dose was too high. In the other, there may have been multiple causes.

There has been a study where conventionally fractionated salvage IMRT with a dose as high as 80 Gy has been used with low toxicity. A recent study using moderate hypofractionation for salvage (51 Gy/ 17 fx) also boasted low toxicity levels among treated patients.

They will monitor both physician-reported toxicity and patient-reported toxicity (urinary, rectal, and sexual). If the rate of grade 3 (serious) toxicity is higher than 20%, accrual will be halted and the study subjected to careful review. If the rate is higher than 30%, the study will be terminated.

Dose Constraints

The investigators have put together a set of very tight dose constraints for organs at risk. Organs at risk include the bladder, the front and back of the rectum, the small intestines, the penile bulb and the femoral head. They also included "point dose constraints": the maximum radiation exposure to even a millimeter of the organ at risk. Because of individual anatomy, it may not always be possible to simultaneously meet all dose constraints. In those cases, the physician will decide if the deviation is material, and if it is, he may lower the dose as low as 30 Gy.

Image Guidance

The prostate bed consists largely of loose and highly deformable tissue. Although some radiation oncologists (e.g., at UCSF) use fiducials or transponders for salvage image guidance, most find that they do not stay in place. This has not been a big issue for salvage IMRT because a few "misses" will not contribute materially to toxicity, but it may be a larger issue for salvage SBRT. One way around this is to have the doctor monitor the position of the soft tissue throughout each treatment, and manually realign the beams whenever the position of the tissues deviates from the planning image. The problem is that  manual realignment is time consuming. The patient is lying on  the bench with a full bladder, which may be difficult to hold in. Also, the more time that passes during a treatment, the more opportunity for bowel motion to occur. The lack of intrafractional image guidance remains a concern in this clinical trial that the investigators are well aware of.

A related issue occurs when the pelvic lymph nodes are simultaneously treated. The lymph nodes may move independently of the prostate bed, so it may be impossible to hit both areas simultaneously with pinpoint accuracy. The investigators are using the pelvic bones as landmarks.

Most importantly, all patients must have a full bladder to lift it up and help anchor organs in place. in addition, enemas are required before each treatment, and if the bowels are at all distended, treatment will be discontinued.

Risks

As with any clinical trial, patients take a risk in trying a new treatment. There is also a learning curve that doctors go through in trying out a new therapy.  I, myself, chose to participate in a clinical trial of primary SBRT when there were only 3 years of reported data. I judged the potential benefits worth the risk for me. It was also important to me that the treating radiation oncologist (Dr.King) had been using SBRT for prostate cancer longer than anyone else. Every patient should be well aware of the risks before agreeing to participate in a clinical trial. Patients who are looking for a shorter duration treatment with less toxicity risk may wish to be treated at the University of Wisconsin or in a clinical trial at the University of Virginia (discussed here).

Ac-225-PSMA-617 (update)

We now have some details of the clinical trial of Ac-225-PSMA-617 in advanced prostate cancer patients. Kratchowil et al. reported on 40 patients who received this treatment at the University of Heidelberg. All patients had failed multiple therapies and were expected to have 2-4 months median survival (see this link). They received 3 cycles of Ac-225-PSMA in two-month intervals.

• 11 patients did not complete 3 cycles
• 5 discontinued due to non-response
• 4 discontinued due to xerostomia (dry mouth)
• 2 did not survive 8 weeks.

Among the 38 surviving patients:

• 87% had some PSA decline
• 63% had a PSA decline greater than 50%
• Tumor control lasted 9.0 months (median)
• 5 patients had a response lasting more than 2 years
• Previous therapies with abiraterone lasted 10.0 months, docetaxel lasted for 6.5 months, enzalutamide for 6.5 months, and cabazitaxel for 6.0 months

These outcomes are impressive for a therapy given when all other therapies have failed. It is unclear whether it is better than Xofigo, the only approved radiopharmaceutical for metastatic castration-resistant prostate cancer. Xofigo only attacks cancer in bones, whereas Ac-225-PSMA attacks prostate cancer anywhere in the body.

(Update 5/19/2019)

Sathekge et al. reported the outcomes on 73 mostly chemotherapy-naive and abiraterone/enzalutamide-naive metastatic castration-resistant patients treated with Ac-225-PSMA-617 in South Africa. Most patients had 3 treatment cycles (every 2 months). Subsequent doses were lower to prevent side effects. PSA and metastatic activity was tracked using Ga-68-PSMA-617 PET scans.

• 83% of patients responded to treatment
• in 70% of patients, PSA declined by over 50%
• PSA declines of over 50% predicted longer progression-free survival and overall survival
• In 29% of patients, all lesions disappeared
• During follow-up, 23 patients (32%) had disease progression and 13 (18%) died of prostate cancer
• Progression-free survival was 15 months (median)
• Overall survival was 18 months
• Xerostomia (dry mouth) occurred in all 85% of patients, but it was not severe enough to stop treatment
• Anemia occurred in 27 patients (37%); none grade 4
• Grade 3 or 4 renal toxicity occurred in 5 patients with pre-existing renal impairment

This study suggests that Ac-225-PSMA-617 can be beneficial in patients who have not been heavily pre-treated. It also shows that xerostomia can be mitigated by reducing the subsequent doses given, and that for most patients, side effects are not severe enough to stop treatment. Lu-177-PSMA is now in a Phase 3 clinical trial at multiple sites in the US.

When can ADT be safely avoided with salvage radiation therapy?

Two randomized clinical trials (GETUG-AFU-16 and RTOG 9601) proved that adding at least some ADT to salvage radiation (SRT) improved outcomes. "Some ADT" was 6 months of goserelin in the GETUG-AFU-16 trial, and two years of bicalutamide in the RTOG 9601 trial. Retrospective studies suggest improved outcomes as well (see this link and this one). On the whole, adjuvant ADT improves SRT outcomes. But is there a subgroup of patients, especially those treated early enough, in whom adjuvant ADT can be safely avoided?

This was the subject of a retrospective analysis by Gandaglia et al. They examined the records of 525 post-prostatectomy patients treated with SRT at six international institutions between 1996 and 2009. Inclusion criteria were:

• Undetectable PSA (<0.1 ng/ml) after prostatectomy
• Biochemical recurrence - two consecutive PSA rises above 0.1 ng/ml
• PSA mostly ranged from 0.2 to 0.9 ng/ml (median 0.4) at the time of SRT
• No detected lymph node metastases

There were 178 patients who received adjuvant ADT (median 15 months) and 347 who had SRT without ADT. Compared to those who received no ADT, those that did were:

• Similar in age, initial (pre-op) PSA, and Gleason score
• More likely to be stage T3b/4
• Less likely to have positive margins
• Received higher SRT dose (70 Gy vs 66 Gy)

There were 8 years median follow-up for those who had no ADT, and 12 years median follow-up for those who had adjuvant ADT. The authors compared the actual 10-yr metastasis rate to the predicted 10-yr metastasis rate based on PSA at SRT, Gleason score, stage, positive margins, SRT dose, and whether lymph nodes were treated. They found that:

• Only those with a 10-year probability of distant metastases greater than 1 in 3 benefited from the addition of ADT
• The benefit grew exponentially with increasing risk
• Adjuvant ADT only benefited those with higher PSA (≥0.4 ng/ml), Gleason score 8-10, stage T3b/4. 
• Higher SRT dose and whole pelvic SRT improved outcomes independently of whether adjuvant ADT was used.

It should be noted that high-dose SRT and whole pelvic treatment were used in a minority of cases, and there is a significant risk of selection bias in this study.

The authors conclude that a higher radiation dose alone may be sufficient to treat many patients with a recurrence detected early enough, but for those with aggressive tumor characteristics, adjuvant ADT will improve outcomes measurably. While this was not proved with a randomized trial, it does suggest that adjuvant ADT will not be necessary in all cases of SRT. Patients who are undecided may wish to have a Decipher genomic classifier done on their prostate tissue to determine their 10-year risk of metastases.

Is ADT still needed for high risk patients receiving brachy boost therapy?

Brachy boost therapy (external beam plus a brachytherapy boost to the prostate) is the gold standard for high risk patients, reporting the best oncological outcomes of any therapy. While long-term adjuvant ADT has proven to be beneficial in prolonging survival in high risk patients when used in conjunction with dose-escalated external beam radiation (DART 01/05 GICOR), there has never been a randomized trial to determine if there is any benefit to ADT when used with brachy boost therapy.

All we have to go by are several single or multi-institutional studies and one large database analysis. Almost all of the studies so far show no effect to short-term (4 months, starting 2 months prior and running concurrent with the radiation therapy) adjuvant ADT.

Two of the studies used a boost of low dose rate brachytherapy, predominantly using Pd-103 seeds. Dattoli et al.  found there was no significant difference in 16-year PSA progression-free survival (PSA-PFS) whether 4 months of ADT were added or not. D'Amico et al. also found no significant difference in 8-year prostate cancer specific mortality (PCSM) with the addition of ADT. However, they felt that it was "approaching significance" (p=.08) and might become statistically significant with longer follow-up. In contrast to the Dattoli study, the D'Amico study did not treat the pelvic lymph nodes.

A recent analysis of the large National Cancer Database by Yang et al. did not detect any benefit to adding ADT on 8-year overall survival (OS). The database lacks specific information about type of brachytherapy, radiation doses, duration of ADT, and whole-pelvic treatment,

Several studies that used high dose rate brachytherapy as a boost also looked at this issue retrospectively. Demanes et al. was the earliest of those studies. They found no difference in 10-year PSA-PFS in their 113 high risk patients treated between 1991-1998. Several subsequent studies confirmed those findings. Galalae et al. concatenated the databases from 3 institutions: Kiel University, University of Washington Seattle and William Beaumont Hospital. Short-term adjuvant ADT failed to demonstrate improved 10-year PSA-PFS in the 359 high risk patients treated between 1986 and 2000. And the lack of effect was demonstrated at all three institutions. Kotecha et al. also failed to find any differential improvement in 5-year PSA-PFS among 61 high risk patients treated with HDR brachy boost at Memorial Sloan Kettering between 1998 and 2009.

There has been one "outlier" study. Schiffmann et al. reported on 211 consecutive high-risk patients treated at the University Medical Center Hamburg-Eppendorf from 1999 to 2009. After 10 years, the biochemical recurrence-free survival was 50% with the adjuvant ADT but only 39% without it - a very statistically significant and meaningful difference. However, even the "improved" outcome seems low compared to the ASCENDE-RT trial where everyone got early neoadjuvant and adjuvant ADT. In that trial, the 9-year PSA-RFS for high risk patients receiving the trimodality therapy was 83%. Another multi-institutional study of HDR-brachy boost therapy reported 10-year PSA PFS of 85% with ADT and 81% without ADT in high risk patients. It is plausible that the patients in the Hamburg study had more advanced disease and had more undetected micrometastases compared to the other studies.

The following table summarizes the treatments given in the aforementioned studies, and whether there was a statistically significant improvement (p<.05).

Relative BED is the biologically effective radiation dose as a percent of the BED of 79.4 Gy of IMRT in 44 fractions.

Short-term vs. Long-term Adjuvant ADT

ADT is believed to have two effects when used in conjunction with radiation. Used before radiation begins (neoadjuvant use) and during radiation treatments (concurrent use), it radio-sensitizes the cancer. Lab findings suggest that it interferes with cancer cell repair of the induced DNA double-strand breaks. Used after radiation (adjuvant use), ADT is believed to "clean up" any remaining local micrometastases that survived. The death of cancer cells from both the radiation and the ADT dumps antigens into the serum that may activate T-cells. Those T-cells may hunt out and destroy small amounts of cancer cells nearby (the bystander effect) or systemically (the abscopal effect).

The bulk of the above retrospective studies suggest that the radiosensitizing effect is unnecessary with the very high radiation doses given with brachy boost therapy. However, what remains to be shown is whether long-term ADT might confer any additional benefit. The DART 01/05 GICOR trial proved that there was a significant benefit to 28 months of ADT compared to 4 months in high risk patients treated with dose-escalated EBRT. It is possible that while short-term ADT may have no benefit, long-term ADT combined with brachy boost therapy might.

TROG 03.04 RADAR was an Australian randomized trial that was designed to detect whether Zometa and longer duration of ADT (18 months vs 6 months) could provide better cures when combined with varying doses of radiation (radiation dose received was stratified but not randomized). Some of the patients received brachy boost therapy. In general, it found that higher radiation doses combined with longer duration of ADT provided the best outcomes. However, among those patients who received HDR brachy boost therapy, there was no significant difference in local progression (fig.2 - showing overlapping standard error bars) whether they received 18 months or 6 months of ADT. Future follow-up may reveal whether long-term ADT prevents distant progression.

The very high rates of cancer control (around 80%-85%) using brachy boost therapy may be as high as we can reasonably hope for, given that there will always be some patients with undetected occult micrometastases.

Better patient selection

High-risk patients are usually given a bone scan and CT to help rule out distant metastases. Bone scans are non-specific to prostate cancer and are not very sensitive when the PSA is below 20 ng/ml. CT scans detect metastases larger than about 1.2 cm, but most metastases are smaller than that. The newly-approved Axumin PET scan, and the experimental PSMA-based PET scans now in clinical trials may be able to detect those distant metastases earlier. However, there are currently no PET scans approved for high-risk patients outside of clinical trials (they are only approved for recurrent and advanced cancer patients). In the future, those high-risk men in whom metastases have been detected via PET scans may be better candidates for systemic therapies, while those in whom no metastases have been detected may be better candidates for brachy boost therapy. It may be economically justifiable to use PET scans for this purpose. Perhaps we will see another 5-10% increase in cancer control rates, even without ADT, with better patient selection. A recent analysis of recurrent patients after prostatectomy diagnosed using the Ga-68-PSMA PET/CT found that 12% had previously undetected metastases outside of the radiation treatment field.

Dose Escalation

At the high biologically effective doses (BEDs) used in all the brachy boost studies, there does not seem to be a significant interaction between dose used and whether ADT was effective. The Dattoli study had the lowest BED, but no benefit to added ADT, while the Galalae study had the highest BED, but also no benefit to added ADT. The Hamburg study had high BED but did demonstrate a benefit to added ADT. All of the brachy boost studies seem to have adequate radiation doses.

Whole Pelvic Radiation

It is possible that pelvic lymph nodes are best treated with a combination of radiation and ADT.  Bittner et al. looked at 186 high risk patients treated with the brachy boost  therapy. The 10-year PSA-PFS was:

• 94% if they received both whole pelvic radiation and ADT
• 82% if the received whole pelvic radiation without ADT
• 90% if they received ADT without whole pelvic radiation
• 75% if they received neither ADT nor whole pelvic radiation

ADT seemed to have a bigger effect than whole pelvic radiation. This may be because the whole pelvic radiation dose is inadequate. The doses given to the pelvic lymph nodes are quite a bit lower (about 50 Gy in 28 fractions) than the dose to the prostate. If Dr. King is right that prostate cancer is inherently radioresistant and requires a higher lethal dose (about 79.2 Gy/44 fx) to be effective, even when the cancer is only in the prostate bed (see this link), it is possible that pelvic lymph nodes require a higher dose as well. Because of the potential bowel toxicity of escalated pelvic doses, adjuvant ADT may be necessary to achieve effective cell kill rates without dose-limiting toxicity. We saw in a recent analysis that, in the salvage situation among patients with GS 8-10, whole pelvic radiation and ADT both had significant benefits. Whether whole pelvic radiation is effective in high risk patients treated with brachy boost therapy and ADT is the subject of a major ongoing randomized clinical trial (RTOG 0924).

Retrospective vs Prospective Trials

All of the published studies so far have been retrospective and are therefore subject to selection bias: those who received the ADT had more progressed disease than those who received the brachy boost without ADT. Therefore, it will always be impossible to convincingly resolve this issue without a prospective randomized clinical trial.

Patient decisions

Until we have definitive results from randomized clinical trials, the decision over whether to add ADT to brachy boost therapy will be challenging. Many patients are persuaded by the extra insurance ADT provides, and that only a short course seems to be necessary. Others are so ADT-averse that even a short course is unthinkable, especially with no concrete evidence of efficacy.

The decision over whether to include the whole pelvic area in the external beam radiation field may be an easier decision. High risk patients have a significant probability that there are small metastases harbored in pelvic lymph nodes. Recent studies have shown the treatment field must be wider than  was previously thought. For some patients with anatomical abnormalities, low visceral fat, and a history of bowel disease, this too may present a challenging decision.

Salvage whole pelvic radiation after cancerous pelvic lymph nodes have been found

Is it still worthwhile to attempt salvage radiation (SRT) after positive pelvic lymph nodes (PLN) have been pathologically detected (stage pN1)? Traditionally, patients with PLN dissection (PLND)-diagnosed pN1 prostate cancer have been considered to have incurable systemic disease. Therefore, they were either observed until distant metastases were identified or started on lifelong androgen deprivation. Retrospective studies of the benefit of salvage whole pelvic SRT for pN1 patients have been equivocal: Abdollah et al. and Rusthoven et al. showed a benefit to salvage RT, but Kaplan et al.showed no benefit.

(Update 9/25/2022) Fonteyn et al. reported the results of the first randomized clinical trial, the PROPER RCT. Unfortunately, the trial did not reach its recruitment targets (n=64) and follow-up was shorter than planned.

• All patients had 1-4 positive PLNs found via PLND, most had 1 positive PLN
• Most (75%) also had prostatectomy, 64% had positive surgical margins

Patients were randomized to 2 years of ADT and either:

• Whole pelvic RT (as high as common iliac LNs) (WPRT), or
• Prostate bed-only RT (boost dose was allowed for known sites of recurrence) (PORT)

After 3-years of follow-up:

• Biochemical recurrence-free survival was 92% for WPRT vs 79% for PORT
• Acute grade 2+ gastrointestinal (GI) toxicity was 45% for WPRT vs 15% for PORT
• Late-term grade 2+ gastrointestinal toxicity was 21% for WPRT vs 3% for PORT
• Acute grade 2+ urinary toxicity was 52% for WPRT vs 48% for PORT (no diff.)
• Late-term grade 2+ urinary toxicity was 41% for WPRT vs 42% for PORT (no diff)

GI toxicity was probably increased by the wide margins used (5 mm) and by the fact that radiation was given on top of surgically dissected tissue. Such extended PLND is rarely done outside of Europe. The SPPORT and POP-RT trials, which did not include previous PLND, found no increase in GI toxicity. Now that PSMA PET/CT is available for recurrent patients, toxicity will probably be lower. The new MRI-targeting linacs (Viewray MRIdian and Elekta Unity) can control for intestinal motion that causes toxicity. Also, there may be an opportunity for better oncological results if para-aortic lymph nodes are also treated (see this link). A STAMPEDE trial found that 2 years of abiraterone increased oncological results.There may also be an opportunity to enhance results with apalutamide.

In an analysis of the National Cancer Database of 7,791 prostatectomy patients (treated from 2003-2010) who were staged pN1 after PLND, Zareba et al. found that most (63%) were initially observed without treatment, and an additional 20% received androgen deprivation (ADT)-only within a year of diagnosis. Only 18% received SRT, most of those (72%) with adjuvant ADT. Those treated with whole pelvic SRT+ADT had worse disease characteristics than those who were observed only: higher Gleason score, higher stage, higher positive surgical margin rate, and greater number of positive lymph nodes.

After 5.9 years median follow-up on 3,680 patients:

• Treatment with whole pelvic SRT+ADT decreased 10-yr mortality by 31% compared to observation only, and by 35% compared to ADT-only.
• Treatment with ADT-only or SRT-only was not associated with an increase in survival

Touijer et al. reported on 1,388 pN1 patients treated at three top institutions: Memorial Sloan Kettering (MSK), the Mayo Clinic, and San Raffaele Hospital in Milan. The MSK cohort was primarily only observed, the Mayo cohort primarily received lifelong ADT-only, and the Milan cohort was primarily treated with whole pelvic SRT+ADT As in the Zareba study, SRT+ADT patients had worse disease characteristics.

After 5.8 years median follow-up:

• Treatment with whole pelvic SRT+ADT decreased 10-yr mortality by 59% compared to observation only, and by 54% compared to ADT-only.
• Those with worse disease characteristics benefited the most.
• Treatment with ADT-only was not associated with an increase in survival compared to observation, although prostate cancer-specific survival was increased.

Zareba and Touijer did not report the toxicity of the salvage treatment, but with improved external beam radiation techniques and scrupulous image guidance, toxicity has been improving.

Zareba and Touijer had very similar outcomes. Although they were both retrospective studies rather than prospective randomized trials, it should be noted that the selection bias that typically plagues retrospective studies favored those who did not receive SRT+ADT. In spite of their worse disease characteristics, the patients who received pelvic SRT+ADT survived longer.

Recently we saw a similar advantage to pelvic SRT+ADT even in men who were not diagnosed as stage pN1 with a PLND (see this link). Taken together, these studies indicate a marked survival advantage to treating the whole pelvic area in men with pathologically diagnosed high-risk prostate cancer post-prostatectomy. A previous study found that among men with pN1, the ten-year incidence of distant metastases was 35%, suggesting that spread may be confined to pelvic lymph nodes for some time. This creates a unique window of opportunity during which salvage treatment may still be curative.

We have also seen evidence that high-risk patients with imaging-detected positive lymph nodes benefited from whole pelvic radiation as primary therapy (see this link).

These studies also constitute better evidence than we currently have that whole pelvic radiation with ADT is a better idea than picking off lymph nodes one at a time (for which we have no evidence of survival benefit). As we have seen (see this link), our ability to detect all cancer-infected lymph nodes is poor.

There are several variables that the patient and doctor must decide upon, and for which there is no clear evidence: duration of adjuvant ADT, amount of radiation, and the pelvic lymph node field. Clinical trials show that at least 6 months of adjuvant ADT with SRT even without lymph node involvement increases oncological effectiveness, the optimal duration is unknown and may vary with disease characteristics (see this link). The amount of radiation to the pelvic lymph node field seems to be about 50 Gy in most cases, and the amount given simultaneously to the prostate bed will ideally be at least 70 Gy (see this link). The extent of the treated area has been questioned recently. Studies show that infected lymph nodes are often missed in the common iliac area (see this link). There will be variations due to individual anatomy and known bowel sensitivity.

(Update 4/25/21) A major Phase 3 randomized clinical trial (INNOVATE) in 141 locations will determine whether intensifying the hormonal side of the treatment with 2 years of Zytiga+Erleada+ADT has better outcomes than 2 years of ADT. They prefer detection with an Axumin scan but allow PSMA and C-11 Choline too. The whole pelvic radiation dose will be determined by the treating radiation oncologist.