Testosterone to TREAT prostate cancer - are they crazy? No - it just may work. (mCRPC)

(frequently updated)

Background

When prostate cancer metastasizes and becomes castration-resistant (mCRPC) after a period of androgen deprivation therapy (ADT), a number of biochemical changes to the androgen receptor (AR) take place within the cancer cell. Among those changes:

• The androgen receptor (AR) multiplies on the cancer cell surface so that even the smallest amount of testosterone or other circulating androgens can activate it.
• Even without an androgen ligand, the androgen receptor moves from the surface of the cell to the inside where it is protected. These internalized androgen receptors play a role in encouraging cell replication and in self-destruction (apoptosis) of cells in which the DNA  has become irreparably damaged.
• The cell manufactures its own androgens internally. These activate the internalized androgen receptors.
• The androgen receptor mutates into truncated versions that can be activated by a host of other molecules (other than testosterone), or don't require other molecules at all to activate it. Recently, researchers at Johns Hopkins identified a version called the "AR-V7 splice variant" that allows the cancer cell to multiply even when all androgens are completely eliminated. It is induced by long term androgen deprivation (see this link).

There may also be tissue-based effects. This means that, in a tumor, there are a variety of cell types. Castration resistance is not an all-or-none situation. Some cells within any given tumor will always remain hormone sensitive. Some cells, like cancer stem cells, have never been hormone sensitive. All of these cell types interact. Hormone-sensitive cells signal castration-resistant cells to become more like them. At the same time, castration-resistant cells signal hormone-sensitive cells to become more like them. Over time, the hormone-sensitive cells (being the ones that are killed by ADT)  lose the battle as the equilibrium shifts towards castration resistance.

How testosterone can help

Supraphysiologic doses, meaning serum levels greater than 1000 ng/dL, may help in several ways:

• Testosterone prevents the androgen receptor from multiplying on the cell surface, and decreases the  number of androgen receptors already there, thereby increasing the cancer cell's sensitivity to subsequent androgen ablation (see this link). It also prevents the cell from becoming super-sensitized to androgens.
• Inside the cell, high levels of testosterone prevent the internalized androgen receptors from encouraging cell replication - too much testosterone, as well as too little testosterone, discourages cancer cell replication (see this link).
• High levels of testosterone and other androgens may induce damage the cancer cell's DNA (see this link). One of the interesting hypotheses is that combining high testosterone with a chemotherapy that is known to cause DNA damage will be particularly effective (see below).
• Testosterone may be able to reverse the AR-V7 splice variant that is known to cause resistance to even second-line hormonal therapies like Zytiga and Xtandi (see this link).
• On the tumor tissue level, testosterone supports the growth of hormone-sensitive cells while destroying castration-resistant cells, as described. This shifts the equilibrium back towards androgen deprivation sensitivity.
• Selective Androgen Receptor Modulators (SARMs) may be able to provide similar benefits without some of the drawbacks (see this link).

Why can't we just give continuous high doses of testosterone?

It's been known for a while that testosterone plays a role in keeping healthy prostate cells healthy. We have observed that hypogonadal men (men who have low natural levels of testosterone) are more likely to have prostate cancer, and more virulent types. For a thorough recent review of this subject, see this link. In fact, one pilot study showed that men with mCRPC who had higher plasma testosterone levels (but still at castration levels) survived twice as long. They responded better to chemotherapy as well (see this link).

In 2009, Robert Liebowitz et al. reported on 96 patients who received very high dose testosterone replacement therapy (TRT) after some kind of prostate cancer treatment. For 59 of those men, the only treatment had been androgen deprivation. 12% were detectably metastatic. 60% had PSA progression while on TRT, but few had metastatic progression in that time period. For most of those, discontinuing TRT reversed the PSA progression.

There was a small (12 man) safety trial at Memorial Sloan Kettering. None of the men achieved supraphysiological serum testosterone levels from the transdermal gel they used. One man had to discontinue when he experienced spinal pain, but there weren't any other major side effects. Of the 12 men, 7 had decreased PSA (one had a 50% decrease). The other 5 had increased PSA, 2 by more than 50%. There was no regression of metastases in any of the men.

Other small trials of TRT alone had mixed results (see this link and this one).

So TRT alone doesn't seem to work. Both effects are necessary: (1) the TRT re-establishes hormone sensitivity, and then (2) the ADT kills off the hormone-sensitive cancer cells. For disease stabilization or regression, it seems to be necessary to alternate TRT with ADT. This is called bipolar androgen therapy (BAT).

I'm on intermittent hormone therapy - doesn't that accomplish the same thing?

Unfortunately, no. It had been hoped that intermittent ADT would accomplish two benefits:

1. Delay the development of castration resistance, and thereby prolong survival, and
2. Give men a break during which quality of life would improve temporarily

In fact, it accomplishes neither for most men. Intermittent ADT is sometimes inferior to continuous androgen ablation, perhaps especially for those with low metastatic burden. Castration resistance occurs at the same time with either intermittent or continuous ADT, and intermittent has not been shown to prolong survival.

After a long while on ADT, it takes a long time for a man's testicles to recover the ability to generate amounts of testosterone that are adequate to recover libido and help a man feel better. As far as the cancer is concerned, the cancer couldn't adapt if it were suddenly shocked by a large surge of testosterone. But during the "off-cycle,"as the amount of testosterone slowly increases, his cancer is able to adapt.  The cancer consequently thrives on the incremental increases rather than being killed by it. By the time the testosterone reaches a level that makes a measurable difference to his quality of life, the cancer has proliferated. His PSA has then gotten so high that the ADT "holiday" must be ended.

It sounds good in theory, but does it work in clinical practice?

Schweizer et al. conducted a pilot test at Johns Hopkins. They treated 16 asymptomatic men who were diagnosed a metastatic and castration-resistant. They were all still on ADT. They gave the men high doses of injected testosterone and treatment with the chemo drug etoposide (see above), which is normally ineffective in treating prostate cancer. After at least 3 cycles:

• Half of them enjoyed a decline in PSA, most of those by more than a 50% decline
• Half had a radiographic response, including 1 patient who had no discernable metastases
• Half the patients did not respond at all, and PSA continued to rise
• Responders had a higher pre-BAT PSA than non-responders
• 10 of 10 patients (100%) responded to second-line ADT (Xtandi, Zytiga or Casodex) after BAT (some were resistant to those therapies before BAT)
• 3 patients had severe toxicity attributable to etoposide.

It appears that BAT may at least delay progression in at least some men with mCRPC. It seems to resensitize their cancers to hormonal agents, even when it didn't succeed in decreasing PSA or evident (radiographic) progression. It does not increase survival (see the TRANSFORMER RCT below). However, the men periodically enjoyed enhanced quality of life from periodic high levels of testosterone. It's unclear whether etoposide chemotherapy added much to the response.

How can we tell who will respond and who will get worse?

Markowski et al. reported on 6 men treated with BAT. A PSMA PET scan (DCFPyL) 3 months into BAT treatment revealed that 3 of them had already progressed to having new metastases.

Before it can gain widespread use, is imperative that predictive biomarkers be found. So far, genomic analysis has failed to discover any.

Can it overcome resistance to Zytiga or Xtandi?

(Update 6/2017) Denmeade's group reported on 30 minimally symptomatic mCRPC men who had progressed on Xtandi.

• 30% saw PSA reduced by at least 50%
• 43% saw PSA increase from baseline; in 17%, PSA more than doubled.
• 36% had some regression of disease
• Median 8.6 months of radiographic/clinical progression-free survival
• 54% responded to re-challenge with Xtandi with a subsequent drop in PSA by at least 50% and progression-free survival of 4.8 months
• A third of those with the resistant AR-V7 mutation responded to BAT, and had lowered AR-V7 levels
• 2 converted from AR-V7 positive to AR-V7 negative
• There were adverse side effects while on BAT. Transient pain flare was the most common, affecting 40%. A few men suffered very serious side effects: pulmonary embolism, heart attack, urinary obstruction, gallstones and fatal sepsis.

(Update July 2020) In the RESTORE randomized clinical trial (RCT), the researchers are investigating whether BAT can restore sensitivity to Zytiga and Xtandi to mCRPC men who have already progressed while using those. They are excluding those who have already had chemotherapy, and no chemo is used in this trial.  They give monthly testosterone injections until there is radiographic progression. The RESTORE trial found that BAT was able to restore responsiveness to Xtandi but much less to Zytiga.

• Following testosterone therapy, PSA declined by 50% in 30% of the group who'd previously taken Xtandi, and in 17% of the group who'd previously taken Zytiga. On these small groups, the difference wasn't statistically significant.
• After BAT, PSA declined by ≥50% in 68% on rechallenge with Xtandi and lasted 13 months
• After BAT, PSA declined by ≥50% in 16% on rechallenge with Zytiga and lasted 8 months
• There was no benefit to rechallenge with either in men with the AR-V7 mutation

(Update December 2020) The "C-arm" of the RESTORE trial comprised 29 castration-resistant (mostly metastatic) patients who received only ADT but no second-line hormonal therapies. 

• Only 4 men (14%) had a PSA decline ≥50% due to the testosterone therapy
• Only 4 men had a reduction in their metastases. All of those had lymph node metastases only.
• Testosterone therapy lasted for 9 months (median) before radiographic progression was detected
• Maximum PSA response was achieved in 56 days. Only 7 patients had any PSA reduction.
• PSA more than doubled in 52%, and increased markedly in 14% more.
• 31% had some radiographic reduction of metastases.
• Median radiographic progression-free survival was 8.5 months
• Musculoskeletal pain was experienced by 40%
• Other prevalent side effects were: hypertension (21%), breast tenderness (21%), leg swelling (17%), fatigue (14%), and difficulty breathing (10%). One patient died of a stroke.
• 18 patients later received Zytiga or Xtandi, with excellent results.
• There weren't any discernable genomic determinants of response.

Based on the RESTORE trial, this trial suggests that BAT should be reserved for patients who:

1. have already progressed on Xtandi, or 
2. a short duration of BAT may make the first use of Xtandi last longer. 

Both of those hypotheses should be tested in larger trials. It also brings into question whether PSA reduction should be used as an endpoint. PSMA PET/CT may be a better indicator of early progression on BAT (see this link). There is still no clue as to why only 31% respond.

In the TRANSFORMER RCT,  195 chemo-naive mCRPC men who failed therapy with Zytiga were randomized to receive either BAT or Xtandi. Everyone crossed over to the therapy they didn't previously get. With up to 2 years of follow-up:

• Comparing BAT to Xtandi (before crossover), there were no significant differences in the time to clinical or radiographic progression (5.7 months in both groups) or reduction in PSA by ≥ 50% "PSA50" (28% and 25%)
• After crossover, PSA50 was 78% for Zytiga->BAT->Xtandi vs 23% for Zytiga->Xtandi->BAT
• After crossover, PSA-progression-free survival was 11 months for Zytiga->BAT->Xtandi vs 4 months for Zytiga->Xtandi->BAT
• Those who went from Zytiga -> BAT -> Xtandi survived 37 months vs 29 months for those who went from Zytiga -> Xtandi (not significantly different)
• BAT improved patient-evaluated quality of life
• 3 patients received Keytruda after BAT and did very well. This observation led to the COMBAT trial using a different immune checkpoint inhibitor (Opdivo)
• (update 5/7/24) Patients who never achieved serum T below 20 ng/dl did better with BAT than Xtandi.

Including BAT right after Zytiga failure and then using Xtandi increased the time to PSA progression, delayed radiographic progression, and reduced PSA. But waiting until after a failure on both drugs had no effect. This trial suggests that BAT may be useful after Zytiga but before Xtandi, particularly if T response to ADT has been less than optimal.

(Update Oct. 5, 2022) An exploratory analysis helps to explain why BAT has limited effectiveness (only 20-30% of  CRPC men derive any benefit from BAT), and what might be done to make it more effective. They focussed on the protein called c-MYC, which is known to be upregulated in advanced prostate cancer. They found:

• High androgen receptor (AR) activity is required for BAT to work. Only about ⅓ of CRPC men have high AR activity.
• But AR inhibition first is needed for T to raise its activity
• High AR activity downregulates c-MYC. 
• High doses of testosterone (T) increases AR activity.
• Xtandi (but not Zytiga or other advanced antiandrogens) prevents acquired resistance to T because it upregulates the AR while it inhibits it.

AR activity (requiring tumor biopsy) may be a valuable biomarker.

They are running a clinical trial to test cycling between T and Xtandi after Zytiga failure.

(update January 2021) In the COMBAT trial, 45 heavily-pretreated men who were mCRPC and who have progressed on either Zytiga or Xtandi, received BAT followed by Opdivo (nivolumab - an immune checkpoint inhibitor).

• ⅔ had at least some PSA reduction
• 40% had a PSA reduction ≥ 50%
• Median overall survival was 28 months
• 24% had a measurable reduction in disease; 11% for 11 or more months
• Median radiographic progression-free survival was 5.7 months
• 1 patient had a complete PSA response
• However, in 27% PSA got much worse after BAT
• BAT seems to inhibit MYC - a genetic driver of prostate cancer

This trial suggests that BAT may prime prostate cancer cells so that they are more sensitive to checkpoint inhibitors.

(Updated 9/21/21) 30 heavily-pretreated men who were mCRPC and who have progressed on either Zytiga or Xtandi, received BAT and the PARP inhibitor olaparib. Half had DNA damage repair defects. This was hypothesized based on lab findings.

• ¾ had at least some PSA reduction
• 47% had a PSA reduction ≥ 50% (44% if 2 who dropped out for progression are added)
• 23% had a 12-wk PSA increase ≥50% (28% if 2 who dropped out for progression are added)
• Median progression-free survival was 14.8 months if they were mutation-free vs. 7.5 months if they had the defects.
• 2 patients had a complete PSA response
• 5 of 8 90+% responders were free of DNA damage repair defects
• 3 of 6 90+% progressors had DNA damage repair defects
• 5 patients had serious (grade ≥ 3) toxicity, including one death

This trial suggests that BAT + olaparib achieved good response regardless of DNA damage repair defect status. Excellent responders had mutations of the T53 gene or DNA repair genes (see this link). The cause of responder/non-responder differences remains elusive.

(update 6/3/2022) A small trial suggests that there may be genomic predictors. They found that some mCRPC patients got a better PSA response from BAT if they had germline (inherited) or somatic (tumor biopsy) genomic mutations of the tp53 gene and one of either RBI gene or PTEN gene loss. There are no clear indications - the results were mixed:

• PSA decreased in 10 of 17 men with tp53 and PTEN loss
• in 8, PSA decreased more than 50%
• in 1, PSA became undetectable
• PSA increased in 7 of 17 men with tp53 and PTEN loss
• in 3 of those 7, PSA more than doubled
• PSA decreased in 2 of 2 men with tp53 and RB1 loss
• PSA increased in 3 of 3 men with RB1 and PTEN loss, so tp53 loss seems to be necessary for a BAT benefit

They also pointed out that in the recent trial of cabazitaxel+carboplatin at MD Anderson, the same genomic predictors of success were found. They propose a comparative trial of the 2 therapies in men who have mutations in tp53 and one of the two (either rb1 or pten).

(Update 11/8/2018) A new clinical trial at the University of Colorado, Denver will try transdermal testosterone instead of injections alternating with enzalutamide.

(update 6/2024) A new clinical trial at Roswell Park, Buffalo to restore sensitivity to ARSi.

(Update Jan 11, 2020) A new clinical trial at Johns Hopkins will combine BAT and Xofigo. Prior treatment with chemo and/or no more than one kind of second-line antiandrogen are allowed but not required. Recall that the RESTORE trial suggested that response was limited to lymph nodes only, so Xofigo may be a complementary treatment. Treatments that induce double strand breaks, like BAT and Xofigo, may be complementary, especially when combined with immunotherapy (see this link).

Other clinical trials include combining with Provenge, combining with Carboplatin, and using on patients who have genomic repair defects other than BRCA: ATM, CDK12, or CHEK2.

It will be important to determine, in future clinical trials, which men will respond to BAT and which men will not. Sadly, there may only be a survival benefit in a small subset of patients, although there is a quality of life benefit. Importantly, all clinical studies so far have only been Phase 2 trials in very small groups of patients. Larger trials will be necessary to prove safety and efficacy. There are already concerns about safety, so patients should not attempt BAT outside of a carefully monitored clinical trial.

There may be particular situations where BAT may be an effective therapy, but data are so far lacking: 

• What, if any, is its benefit in men who are metastatic but still hormone-responsive (mHSPC)? (see this link)
• Does it have any benefit in men who have already had docetaxel chemotherapy? 
• Considering that metastases shrank in some men on BAT, should it be tried in symptomatic men as well? 
• What is its effect on AR-V7-positive or negative men? 
• Should it be used in combination with other therapies, such as PARP1 inhibitors, immunotherapies, and radiological therapies? 
• What is the optimal sequencing of therapies? 
• Is there any benefit to BAT  used along with radiation therapy in high-risk men (see this link)?

Salvage Low Dose Rate Brachytherapy (LDRBT) after primary LDRBT failure

Although focal retreatment of the prostate using LDRBT has been used after failure of external beam radiation, there have been very few reports of salvage LDRBT after an initial treatment with LDRBT failed.

In a study at the University of Kentucky (UK), Lacy at al. looked at the records of 21 patients who had been re-implanted with seeds.  They all had a bone scan and CT to rule out metastases and locate areas within the prostate that had less-than-optimal seed coverage. Patient characteristics were as follows:

• ·      Initial low risk: 61percent
• ·      Initially intermediate risk: 29%
• ·      Received EBRT with primary LDRBT: 14%
• ·      Received ADT with primary LDRBT : 33%
• ·      Received ADT with salvage LDRBT: 14%
• ·      Age: 59 (median)
• ·      PSA before primary LDRBT: 6.3 ng/ml (median)
• ·      PSA before salvage LDRBT: 3.5 ng/ml (median)
• ·      Time to biochemical failure: 45 months (median)

Seeds were only added to areas that had poor seed coverage. After 49 months (median) follow-up:

• ·      52% were free from a second biochemical failure
• ·      All of the men who were initially classified as intermediate risk suffered biochemical failure.
• ·      All had an initial decline in PSA, reaching a nadir of 0.7 ng/ml at 15 months (median).
• ·      The remaining 48% exhibited biochemical failure at 25 months (median).
• ·      Urinary symptoms were apparent at 3 months after retreatment but improved back to baseline by 18 months.
• ·      Serious side effects comprised bladder outlet obstruction (1 patient), rectourethral fistula (1 patient), and leiomyosarcoma (1 patient).
• ·      Of the 6 men fully potent at baseline, 5 had some deterioration in erectile function by 18 months after re-treatment.

Several other small studies have demonstrated higher rates of biochemical re-recurrence-free survival (Blasko et al., Koutrouvelis et al., Mahal et al., Hsu et al.). Because of the relatively long time to recurrence after re-treatment (25 months median), those studies probably lacked the length of follow-up necessary to detect the re-recurrence.

As with all attempts at salvage treatment after any kind of radiation failure, two conditions must be met before any such attempt is made:

1.     There must be assurance that the failure is local – in the prostate.

2.     There must be assurance that the cancer has not metastasized outside of the prostate.

Multiparametric MRI-targeted biopsies or saturation biopsies (or the two combined) are best for assuring the first condition is met. A more common option has been a random TRUS-guided biopsy. Some of the newer types of PET scans, such as C11-Choline, are best for assuring that the second condition is met. The more common option is the bone scan with CT.

In the UK study, only bone scans and CTs were used to rule out metastasis, and there were no biopsies done to assure that they were treating a local recurrence. They assumed that there were local recurrences in under-covered areas (“cold spots”). It is likely that their oncological outcomes might have been improved by better patient selection. In the University of California San Francisco (UCSF) study, they used MRI/MRS targeting to biopsy areas for recurrence, and to detect cold spots. Two patients had a second focal brachytherapy re-treatment. Five of the 11 patients failed retreatment at 3 years of followup, but 3 of the 5 had negative biopsy results, indicating that the failure was due to remote metastases. Because of better treatment planning possible with the advanced MRI imaging, UCSF also had minimal treatment-related toxicity. Erectile function was maintained with medication in 67% and without medication in 20%.

Good oncological control after LDRBT failure has been reported using salvage surgery and salvage whole-gland cryotherapy; however, sexual toxicity is high with both, and urinary and rectal toxicity is high with salvage surgery. Salvage focal cryotherapy, as well as other focal ablative therapies may increasingly be used for this purpose. As far as other kinds of re-irradiation goes, there has only been a single case report of salvage SBRT after LDRBT failure. Salvage focal HDRBT may be used for this purpose as well.

written April 25, 2016

Another reason to love your bounces

PSA bounces after primary radiation therapy are a common phenomenon, occurring in a quarter to a third of patients. While some men might prefer to see an uninterrupted PSA decline after treatment, studies have demonstrated an association with improved cancer control. Studies also find higher incidence of bounces in younger men. Perhaps related to that, we now see that there is an association between bounces after brachytherapy and erectile function, sexual activity, and sexual satisfaction.

Matsushima et al. examined the records of 154 patients who had been treated with brachytherapy, and whose sexual function was self-assessed at baseline and continually for up to 3 years. Among those men, 25% experienced a PSA bounce of at least 0.4 ng/ml above the previous PSA reading, and they experienced that bounce a median of 18 months after therapy.

Compared to the men who did not have a bounce, those who did reported higher scores on all measures of sexual performance at baseline and at all time points afterwards. “Bouncers” had higher scores on:

• ·      Erectile function
• ·      Orgasmic function
• ·      Sexual desire
• ·      Intercourse satisfaction
• ·      Total International Index of Erectile Function-15 Score

The authors also conclude: “an occurrence of prostate-specific antigen bounce seems to be more likely in those who are more sexually active.”

While it’s tempting to infer causal relationships, there are many possible reasons for this observation. It’s possible to put forward many hypotheses, none of which are proven:

• ·      Younger men have better sexual performance, and it may just be a coincidence that they are more likely to have bounces.
• ·      Because PSA readings are affected by recent sexual activity, those with bounces had sex closer to the date of their PSA test.
• ·      Sexual activity promotes health of the sexual apparatus, and deters radiation-induced scar-tissue formation.
• ·      Older cells may be more prone to immediate killing by radiation, while cell-cycle arrest, which may delay apoptosis, may be more likely in younger cells.

Whatever the reason behind the association, it provides one more reason not to worry about bounces after radiation therapy.

Better cancer control with radiation vs. surgery in high-risk patients

Researchers at the University of Alabama at Birmingham assigned high-risk patients to receive either external beam radiation therapy with androgen deprivation therapy (RT+ADT) or to receive surgery (RP) with or without adjuvant/salvage radiation. RT+ADT was the clear winner. It’s not a randomized trial, and it is small and retrospective, but it’s worthy of note nonetheless.

Baker et al. reported on 121 patients treated between 2001 and 2014 who were diagnosed with Gleason scores ≥8 (on either biopsy or pathology). 71 patients received RT+ADT according to the following protocol:

• ·      75-77 Gy in 40-42 fractions or 70 Gy in 28 fractions
• ·      All received pelvic lymph node radiation
• ·      Almost all (96%) received ADT for 24 months
• ·      1 patient received adjuvant docetaxel

50 patients who had life expectancies ≥ 10 years, no serious comorbidities, and whose prostate were considered resectable, were offered radical prostatectomy instead of radiation. All patients were seen by both a urologist and a radiation oncologist. Of the 50 RP patients:

• ·      76% also had pelvic lymph node dissection
• o   8±6 lymph nodes were sampled
• o   18% had positive lymph nodes
• ·      88% had adverse pathology: positive margins, seminal vesicle invasion, or extraprostatic extension
• ·      74% were stage T3 at pathology (vs. 4% pre-RP)
• ·      84% were GS≥8 at pathology (vs. 63% pre-RP)
• ·      44% received adjuvant radiation
• ·      24% received salvage radiation
• ·      Those with positive lymph nodes received salvage pelvic radiation
• ·      1 patient received adjuvant docetaxel

After average followup of 74 months for those who originally received RT+ADT and 60 months for those who originally received RP, the 5-year biochemical failure rate was:

• ·      7% for those originally receiving RT+ADT
• ·      42% for those originally receiving RP

The 5-year detection of distant metastases was:

• ·      2% for those originally receiving RT+ADT
• ·      8% for those originally receiving RP

The 5-year use of salvage (permanent) ADT was:

• ·      8% for those originally receiving RT+ADT
• ·      34% for those originally receiving RP

While the researchers did not report on toxicities, it is safe to say that those who received original RP suffered worse toxicities. This is true not only because surgery carries greater risk of incontinence and impotence, but also because 68% of those who originally received surgery received radiation on top of that, and half of those men received ADT with their adjuvant/salvage radiation. Adjuvant/salvage radiation has a worse toxicity profile compared to primary radiation.

The results in favor of initial radiation therapy are particularly impressive because radiation patients in this study had more progressed disease at the time of treatment. They had higher Gleason scores, higher stage, and higher risk of lymph node involvement. They were also considerably older. The results are all the more impressive because the amount of radiation given was low by today’s best practice standards, and because combination therapies of external beam radiation with a brachytherapy boost to the prostate have been proven superior to external beam monotherapy in randomized clinical trials. If anything, the selection bias and treatments in this study should have favored those who were initially surgically treated.

On the other hand, it’s been demonstrated that the limited pelvic lymph node dissection of the surgery patients given in this study is often inadequate to detect the full extent of involvement. They note that they have recently changed their protocol to include extended pelvic lymph node dissection (ePLND) on high-risk RP patients. Sometimes ePLND not only detects the extent of involvement, but may also clear the area of cancer without the need of salvage nodal radiation.  Two additional caveats are that the difference in definitions of biochemical failure and the two years of ADT may affect relative outcomes. However, it is hard to imagine that the long-term effects would enough to change conclusions given the magnitude of the difference.

While this is not the large-scale prospective randomized trial of RT vs. RP that we would like to see, the large variance in outcomes should be considered by anyone trying to decide between radiation and surgery for a high-risk diagnosis.

Safety limits of SBRT dose escalation

In a recent commentary, we saw that the lack of a standard of care for SBRT dose escalation may put patients at risk when dose limits are pushed beyond what is customarily considered effective and safe. Hannan et al. have now published their efficacy findings. Further details of the IRB-approved clinical trial specs are available here.

Between 2006 and 2011, the researchers at several institutions conducted a dose escalation trial utilizing SBRT on 91 men treated for low and intermediate risk prostate cancer. Among those men:

• ·      64% were intermediate risk, defined as:

o   Either GS 6 and PSA between 10 and 20 ng/ml , or

o   GS 7 with PSA≤ 15 ng/ml and clinical stage ≤ T2b

• ·      36% were low risk by the NCCN definition.

All patients received 5 treatments or fractions. The first 15 patients were treated with 45 Gy, the next 15 with 47.5 Gy, the next 15 with 50 Gy. Because that last group did not exhibit their predefined “maximally tolerated dose” in the short term, an additional 47 patients also received the 50 Gy dose.

The cancer control was excellent. At 5 years after treatment:

• ·      98.6% were free from biochemical failure
• ·      100% were free from metastases
• ·      None had died of prostate cancer
• ·      Overall survival was 89.7%

Toxicity was another matter. There were no reports of serious acute urinary toxicity. However, late-term urinary toxicity of grade 3 or greater was reported in 5.5% of patients. For the purposes of their analysis, acute toxicities were those observed within 9 months of treatment, and late-term toxicities were those observed between 9 and 18 months.

Rectal toxicity was reported in detail earlier by Kim et al. and merit a closer look:

• ·      Among those who received 45 Gy there was no serious (grade 3 or higher) acute or late term toxicity.

o   No acute grade 2 toxicity was observed.

o   Late-term grade 2 toxicity was observed in 1 patient (of 15).

• ·      Among those who received 47.5 Gy there was no serious (grade 3 or higher) acute or late term toxicity.

o   Acute grade 2 toxicity was observed in 4 of 15 patients (27%)

o   Late-term grade 2 toxicity was observed in 5 of 15 patients (33%).

• ·      Among the 61 patients who received 50 Gy there was:

o   One case of serious (grade 3) acute toxicity and one case of life-threatening (grade 4) acute toxicity.

o   3 cases (5%) of serious (grade 3) late-term toxicity and 2 cases (3%) of life-threatening (grade 4) late-term toxicity.

o   2 of the patients developed rectourethral fistulae, and 5 required diverting colostomies.

We note that even at the lowest dose level given in this trial (45 Gy), they were delivering much more than the customary SBRT dose of 36.25 Gy. Because this study began with such a high dose, it did not succeed in its objective of finding an optimal dose. It did, however, find the dose that created dose-limiting toxicity. At 50 Gy, they were delivering a dose that is bioequivalent to more than twice the customary and safe IMRT dose (80 Gy in 40 fractions). This is especially troubling when we realize that 36% were low-risk patients who might have delayed treatment with active surveillance.

There are many aspects of this study that are hard to understand. It’s hard to understand why they didn’t start at a more reasonable dose level. Dr. Alan Katz reported excellent cancer control with extremely low toxicity using only 35 Gy (see this link). With the sharp increase in acute grade 2 toxicities at 47.5 Gy, it’s hard to understand why the researchers did not pull the plug before patients were seriously harmed. It’s also hard to understand how the internal review board (IRB) did not question the ethics of this study.

(Update 2/6/2019) In a small (n=26) prospective dose-finding study of 40 Gy (n=9), 45 Gy (n=10) and 50 Gy (n=7) among low and intermediate risk patients, Potters et al. reported freedom from biochemical failure of 92%, 100% and 100% respectively with 67 months of follow-up. There were no Grade 3 toxicities, and toxicity was about equal in all groups. Quality of life returned to baseline in all groups within 2 years.

We have observed (see this link) that there is a lot more to SBRT safety than simply setting the prescribed dose. Careful planning, image guidance and accurate delivery are equally important. In the right hands, SBRT is among the safest and most effective of all radiation therapies, with excellent convenience and relatively low cost. In fact, I chose it for myself.

Is there an optimal treatment schedule for high dose rate brachytherapy?

Protocols for high dose rate brachytherapy (HDR-BT) monotherapy vary. In recent years, practitioners have adopted various schedules for patient and physician convenience. Jawad et al. reported on the HDR-BT experience at William Beaumont Hospital. They treated 494 favorable risk patients using three different treatment schedules. Their definition of “favorable risk” was a Gleason score ≤7 and stage≤T2b and PSA≤15 ng/ml. The 3 treatment schedules they utilized, the number of patients who received each, and the relative biologically effective dose  (BED) were as follows:

1. 38 Gy in 4 fractions (n=319) – 1.29 relative BED 
2. 24 Gy in 2 fractions (n=79) – 1.00 relative BED 
3. 27 Gy in 2 fractions (n=96) – 1.25 relative BED

Dose schedules #1 and #3 delivered much higher relative dose compared to dose schedule #2. The questions addressed by the study are whether the higher dose is justified by greater cancer control, and whether dose increased at the expense of increased side effects.

After 5.5 years median followup for schedule #1, 3.5 years for schedule #2, and 2.5 years for schedule #3, the toxicity outcomes were as follows:

• No difference in clinical outcomes (cancer control) among the 3 treatment schedules.
• Acute (appearing in less than 6 months) and chronic (appearing 6 months or more after treatment) grade ≥2 genitourinary (GU) and gastrointestinal (GI) side effects were similar for all treatment schedules.
• Grade 2 acute GU toxicities:

o   Frequency/urgency: 14%

o   Dysuria (painful urination): 6%

o   Retention: 7%

o   Incontinence: 1.5%

o   Hematuria (blood in urine): 1.5%

• ·      Grade 2 chronic GU toxicities:

o   Frequency/urgency: 20%

o   Dysuria (painful urination): 7%

o   Retention: 4% (Urethral stricture: 2%)

o   Incontinence: 2%

o   Hematuria (blood in urine): 7%

• ·      There was minimal grade 3 GU toxicity
• ·      Grade 2 acute GI toxicities:

o   Diarrhea: 1%

o   Rectal pain/tenesmus: <1%

o   Rectal bleeding: 0%

o   Proctitis: <1%

• ·      Grade 2 chronic GI toxicities:

o   Diarrhea: 1%

o   Rectal pain/tenesmus: 0.5%

o   Rectal bleeding: 2%

o   Proctitis: 1%

• ·      No Grade 3 or higher GI toxicity
• ·      Time to maximal appearance of symptoms was similar across treatment schedules
• ·      They did not report ED rates, which are typically low for HDR-BT.

Given the equivalence of cancer control and toxicity with treatment schedule, and the lack of any effect due to increasing the biologically equivalent dose, there seems to be little basis, other than cost and convenience, for choosing among these treatment schedules, at least with the available follow-up reported here.

Aspects of treatment scheduling that affect the convenience of HDR-BT are the number of implantations of the catheters, and the time frame in which the fractions are delivered.  William Beaumont Hospital uses a single implantation of catheters for all treatment schedules. Schedule #1 involves a longer (overnight) hospital stay because they wait for several hours between fractions for healthy tissue to recover. It also means that anesthesia must be administered over a longer period.

The California Endocurietherapy Center at UCLA has typically used a different protocol. They deliver 42 Gy in 6 fractions, with 3 fractions delivered one week and 3 fractions delivered a week later. This involves 2 overnight hospital stays, with anesthesia each time. Recently, they added a protocol where they deliver 27 Gy in 2 fractions (similar to schedule #3), but those fractions are still inserted a week apart. While this is certainly a cost reduction for the patient, who can now be treated as an outpatient, the patient is inconvenienced by having to go through the full procedure twice. It is a convenience for the treatment team that no longer has to attend the patient over an extended timeframe.

The William Beaumont Hospital experience demonstrates that HDR-BT treatment schedules can be constructed so as to lower costs and increase convenience for patients and doctors, without sacrificing cancer control or quality of life.

Dose-escalated radiation therapy doesn’t impact survival within ten years

Zaorsky et al. conducted a meta-analysis of 12 randomized clinical trials covering data on 6884 patients treated with external beam radiation at various dose levels. Their goal was to determine whether increasing the delivered biologically effective dose made a difference in 5 or 10 year metastasis-free survival, prostate cancer specific survival, or overall survival.

They found that dose-escalated radiation had the following effects:

• ·      10-year freedom from biochemical failure improved by 9.6% in low-risk men.
• ·      10-year freedom from biochemical failure improved by 7.2% in intermediate-risk men.
• ·      There was no corresponding improvement in metastasis-free survival, prostate cancer specific survival, or overall survival out to 10 years.
• ·      Dose escalation was not correlated with increases in acute toxicities.
• ·      Late-term gastrointestinal toxicities increased in patients treated with 3D-CRT.
• ·      Late-term toxicities were lower among patients treated with IMRT despite higher dose levels.

The abstract makes no mention of dose-escalated radiation treatment of high-risk men. We discussed some conflicting  survival data on higher risk patients in a previous commentary (see this link). As we saw, even at the higher risk levels, ten years follow-up was not long enough to detect difference in survival due to dose escalation.

The authors conclude:

“Thus, freedom from biochemical failure is a poor surrogate of overall patient outcomes for trials of RT.”

This is an unwarranted conclusion from the data presented in the abstract. We discussed the issue of surrogate endpoints (like freedom from biochemical failure) and length of follow-up in a previous commentary (see this link). For a newly diagnosed intermediate-risk man, the time frame for development of distant metastases could easily be upwards of 10 years, and a lot longer for low-risk men. The only valid conclusion one can draw from their analysis is that 10 years is too short a time frame to detect any effect of dose escalation on metastasis-free survival, prostate cancer survival or overall survival in these risk groups. Their analysis makes the argument for using surrogate endpoints, rather than against them. Given the long natural history of prostate cancer progression in these risk groups, how else can we gauge the impact of dose escalation within a practical followup timeframe?

The other interesting conclusion is that dose escalation, when delivered with IMRT technology, had no impact on acute or late-term toxicities. This argues for IMRT-delivered dose escalation: since it did not increase toxicity risk, and may increase long-term cancer control, there is no reason not to use it. This holds true even among low risk men who, for whatever reason, have elected not to engage in active surveillance. It also holds true for men with fewer than ten years of life expectancy who, for whatever reason, have elected not to engage in watchful waiting.

Salvage whole-gland cryoablation after radiation therapy failure

At the 17^th International European Association of Urology Meeting, Joseph Chin of the University of Western Ontario presented his analysis of outcomes of 157 patients treated with whole-gland salvage cryotherapy after primary radiotherapy failure between 1995 and 2004. After a median followup of 117 months:

• ·      10-year overall survival was 76%
• ·      10-year metastasis-free survival was 74%.
• ·      Median biochemical disease-free survival was 56 months.
• ·      10-year biochemical disease-free survival was 34%.
• ·      15-year biochemical disease-free survival was 23%.
• ·      Of the 179 complications, 22 (12%) were serious.

While more than 3 in 4 men had a biochemical recurrence after salvage cryotherapy, it’s not at all clear whether any salvage therapy on this group of patients could have increased survival any better or with fewer complications. As far as I’m aware, this is the longest followup that has been reported in a salvage cryotherapy study, but, paradoxically, its greatest strength is also its greatest weakness. Many of the men treated in this study were selected for salvage treatment before we had advanced imaging techniques that might have identified small distant metastases in many of them. Also, cryotherapy has benefitted from technological advances that have reduced morbidity considerably.

There are many outstanding questions:

• ·      How should patients be selected for salvage therapy after radiation?
• ·      Can we use advanced imaging to eliminate those patients in whom distant metastases have already occurred?
• ·      Did the salvage therapy delay progression?
• ·      Is there a survival advantage to salvage whole-gland cryoablation vs. focal or hemi-gland cryoablation?
• ·      Is there an advantage in terms of treatment morbidity to salvage whole-gland cryoablation vs. focal or hemi-gland cryoablation?
• ·      How does salvage cryo compare to other ablative salvage therapies, salvage radiotherapies, or salvage surgery after radiation failure?