Survival benefit to debulking the prostate with radiation in men with low metastatic burden

The term "debulking" denotes the radical treatment (via prostatectomy or radiation) of the cancerous prostate after distant metastases have been discovered. This first randomized clinical trial of debulking with external beam radiation found that there was no overall survival benefit.

Results of the STAMPEDE randomized clinical trial were published in the Lancet. Like the HORRAD trial (see below), they found there was no survival benefit to radiation debulking among all newly diagnosed men with metastases (Stage M1). Unlike the HORRAD trial, they utilized higher radiation doses.

Newly diagnosed men were treated with standard of care (which at the time meant ADT and docetaxel in 18% of the men) and were randomized to no radiation debulking or hypofractionated radiation, consisting of either:

• 55 Gy in 20 daily treatments, or
• 36 Gy in 6 weekly treatments (note: this bioequivalent dose is 15% higher)

However it made a big difference in survival if the men were oligometastatic (1-3 distant metastases). After 37 months median follow-up:

• Survival increased by 32% (hazard ratio = 0.68) in 819 oligometastatic men
• 3 yr survival was 81% with debulking vs 73% without debulking
• No survival increase among the 1,120 polymetastatic men (defined as visceral metastases or 4 or more bone metastases with at least 1 outside the axial skeleton)

Survival increases were also noted among men with only pelvic lymph node metastases (N1M0), in whom whole pelvic radiation may be curative.

Adverse events from the radiation were generally mild:

• 5% had grade 3 (serious) or higher acute urinary or rectal side effects
• 4% had grade 3 (serious) or higher late-term urinary or rectal side effects

Based on this and their other randomized clinical trials, men with lower metastatic burden should be treated with ADT+Zytiga or ADT+docetaxel, followed in 2 months with local hypofractionated radiation. Men with higher metastatic burden should be treated with ADT+Zytiga or ADT+docetaxel (it is unknown whether ADT+Zytiga+docetaxel adds any additional benefit). Metastasis-directed therapy is under investigation.

(Update 2/18/2021) Because controversy exists in how to define "low metastatic burden," Ali et al. undertook a secondary analysis of the STAMPEDE trial. They found that the benefit of RT debulking was greatest in two groups:

1. 1-3 bone metastases (M1b) with no visceral metastases
2. Only non-pelvic lymph node metastases (M1a) with no visceral metastases

The survival benefit dropped off after 3 bone metastases. There was no benefit in anyone with any visceral metastases (M1c). Metastases are counted based on conventional imaging (bone scan/CT), so metastases found on PET scans do not count towards the total.

(Update 6/7/2022) Long-term follow-up (61 months) of the STAMPEDE trial, confirmed earlier findings:

• Survival increased by 36% if low burden
• Survival decreased by 11% if high burden (not statistically significant)
• No difference in quality of life

Boevé et al. reported the results of 432 men with bone metastases at 28 centers in the Netherlands from 2004 to 2014 (the HORRAD trial). They had received no previous treatments. They all had PSA > 20 ng/ml at the start of treatment and were under 80 years of age. They were randomized to receive either:

1. Lifelong ADT (an LHRH agonist, starting with 4 weeks of an anti-androgen)
2. Lifelong ADT + external beam radiation therapy (EBRT) 

The EBRT dose was 70 Gy (35 treatments of 2 Gy each) or 57.8 Gy (19 treatments of 3.04 Gy each), which are biologically equivalent. No whole pelvic radiation or brachy boost therapy was given.

After 47 months median follow-up, the median overall survival was:

• 45 months in the group that received ADT + EBRT
• 43 months in the group that received ADT only

The difference was not significant

The authors also looked at survival differences based on:

• Number of bone metastases (<5, 5-15, >15)
• PSA at diagnosis (greater or less than 60 ng/ml)
• Gleason score
• Stage
• Age
• Performance status
• Painful bone metastases

None made any significant difference in survival.

The time to PSA progression was slightly longer among those who received EBRT (15 months vs. 12 months), but the statistical significance vanished after correction for patient characteristics.

These disappointing results conflict with several retrospective database analyses. This once again illustrates that only prospective randomized clinical trials can prove a causal relation, and that observational studies are confounded by the vagaries of patient selection; i.e., patients who receive debulking in actual clinical practice are the ones who would do better anyway. It is worth noting that a similar thing had occurred with breast cancer. Several retrospective studies had suggested that resection of the breast tumor  plus axillary lymph nodes increased survival even when distant metastases were detected. However, Badwe et al. reported that when women were prospectively randomized to that treatment or no such treatment, there was no survival difference.

Because this trial began over a decade ago, it does not include radiation doses now considered to be curative (around 80 Gy). Nor does it include brachy boost therapy, which was shown to be superior to EBRT alone in high risk patients in the ASCENDE-RT randomized clinical trial. It is also unknown what effect whole-pelvic radiation or metastasis-directed therapy might have had, or whether prostatectomy with or without extended pelvic lymph node dissection (ePLND) may have increased survival.

(update 7/3/22) Dai et al. reported the results of an RCT among 200 men with oligometastatic PCa randomized to ADT alone or ADT with debulking the prostate with radiation or surgery (85% had surgery). After a median follow-up of 48 months:

• Radiographic progression was reduced by 57% by debulking
• Mortality was reduced by 56% by debulking
• PSA progression was reduced by 56% by debulking

These clinical trials began before CHAARTED, STAMPEDE, and LATITUDE clinical trials proved that early treatment with docetaxel and abiraterone improves survival in newly diagnosed metastatic men. It is unknown what effect debulking may have in men pre-treated with those systemic therapies.

Many of these unknowns are being explored in current clinical trials. The randomized clinical trial of debulking at 257 US locations will allow for systemic pre-treatments and either EBRT or surgery. This clinical trial in Canada allows for treatment with surgery, HDR brachytherapy, chemotherapy, and SBRT to metastases. This clinical trial in Europe allows for treatment with  docetaxel, and abiraterone. This clinical trial in Germany randomizes patients to prostatectomy + ePLND or best systemic therapy.

Because radiation and prostatectomy have adverse effects, this study should make patients cautious about having any kind of debulking outside of a clinical trial.

Newly diagnosed, metastatic (M1), but still hormone sensitive - best options

(Frequently Updated)

In the US, only 3% of new patients are newly diagnosed with metastatic, hormone-sensitive prostate cancer (mHSPC). "Metastatic," for the purposes of this analysis only includes distant metastases (Stage M1), but not pelvic lymph node metastases (Stage N1). This group has been the subject of many major randomized clinical trials over the last few years. CHAARTED, in the US, randomized to early docetaxel + androgen deprivation therapy (ADT) compared to ADT alone. STAMPEDE, in the UK and Switzerland,  has published several studies: one on the use of Zometa and Celebrex, one on docetaxel,  one on abiraterone+prednisolone  (updated here) (I'll refer to this combination as Zytiga), and two on debulking the prostate with radiation (one from STAMPEDE and one from HORRAD). They also included men with locally advanced and recurrent prostate cancer, which we will address at another time (see this link). 

LATITUDE was a multinational clinical trial comparing Zytiga+ADT to ADT alone. TITAN was a multinational trial comparing apalutamide (Erleada) +ADT to ADT alone. ENZAMET was a multinational trial comparing enzalutamide (Xtandi) + ADT to early antiandrogens +ADT. ARCHES assessed the effect of enzalutamide on radiographic progression-free survival. TITAN and ENZAMET are discussed in more detail here.

We can look at hazard ratios for overall survival. A hazard ratio (HR) of, say, 0.60 means that the treatment reduced the number of deaths by 40% compared to the standard treatment. Unless it is otherwise noted, the HRs we talk about are all statistically significant with 95% confidence.

Early use of docetaxel

The hazard ratios found for all metastatic men were as follows:
CHAARTED: 0.61
STAMPEDE: 0.81
GETUG-15: 0.90 (not statistically significant)

The hazard ratios for men with high volume mets only were:
CHAARTED: 0.60
GETUG-15: 0.8 (not statistically significant)
STAMPEDE: 0.81 (not statistically significant)

The hazard ratio for men with low volume mets only were:
CHAARTED: 1.03 (not statistically significant)
STAMPEDE: 0.76 (not statistically significant)

GETUG-15 was a French randomized clinical trial. It has been criticized for including men with more advanced disease than CHAARTED. When STAMPEDE showed similar results to CHAARTED, GETUG-15 was largely ignored, and early use of docetaxel became the new standard of care. Some argued that the  results of STAMPEDE and CHAARTED suggest that docetaxel should be considered for among all metastatic men, but a CHAARTED update suggests a benefit only among those with high volume of metastases. However, a STAMPEDE update showed no difference in overall survival or failure-free survival between the two subgroups. The STAMPEDE authors point to their larger trial and that their analysis applies more to newly diagnosed men, whereas the CHAARTED groups had more previously treated men. They advocate early use of docetaxel regardless of metastatic burden. (High volume was defined as visceral metastases or 4 or more bone mets with at least one beyond the pelvis or vertebrae.)

One should resist the temptation to compare HRs across studies. Each study had different patient characteristics, and PSA screening policies differ markedly in those countries. In fact, a recent analysis of the STAMPEDE outcomes of men who were randomly assigned to either Zytiga or docetaxel found that there was no difference in survival between the two treatments (see this link).

Early use of Zytiga

The hazard ratios found for all metastatic men were as follows:
LATITUDE: 0.66
STAMPEDE: 0.62

An unplanned secondary analysis presented at ESMO 2018 and published in European Urology looked at high volume vs low volume, and found it worked equally well in both situations:

The hazard ratios for men with high volume mets only were:
STAMPEDE: 0.60

The hazard ratio for men with low volume mets only were:
STAMPEDE: 0.64

In an 5-year update, there was no difference in mortality depending on whether the patient had many or few metastases:

The hazard ratios for men with high burden patients only were:

STAMPEDE: 0.54

The hazard ratios for men with low burden patients only were:

STAMPEDE: 0.55

Early use of Zytiga+Docetaxel

Overall survival is only available for men with high volume of metastases, but radiographic progression-free survival increased by 2.5 years (from 2.0 to 4.5 yrs) with the addition of abiraterone to docetaxel. Time to castration resistance increased by 1.7 yrs (from 1.5 to 3.2 yrs). 

For men with high volume of metastases, median overall survival increased from 42 months with docetaxel only to 61 months with docetaxel+Zytiga.

See discussion of early results of PEACE1.

Early use of darolutamide (Nubeqa) + Docetaxel

In the ARASENS trial, the "triplet" of ADT+ docetaxel + darolutamide reduced mortality by 32% over ADT+docetaxel (HR= 0.68).

See: discussion of triplet therapy

Early use of Erleada

The hazard ratio for metastatic men was 0.67

Early use of Xtandi

The  hazard ratio for all metastatic men was 0.66

The hazard ratio for men with high volume mets only was 0.74 - not statistically significant

The hazard ratio for men with low volume mets only was 0.48 - statistically significant


Early use of Debulking

The hazard ratios found for all metastatic men were as follows:
STAMPEDE: 0.92  (not statistically significant)
HORRAD:  0.90 (not statistically significant)

The hazard ratios for men with high volume mets only were:
STAMPEDE: 1.07 (not statistically significant)

The hazard ratio for men with low volume mets only were:
STAMPEDE: 0.68 (statistically significant)

Early use of Zometa+Celebrex

The hazard ratios found for all metastatic men were as follows:
STAMPEDE: 0.78 (see this link)

Which is best? 

The early use of Zometa is frowned upon because side effects increase over time. However, if an older man already has osteoporosis, Zometa+Celebrex is a good combination. As long as the patient doesn't have contraindications like heart disease or bad teeth, it is cheap, non-toxic, and reduced risk of death by 22% at the 43-month follow-up. Zometa is usually given along with ADT anyway, so it is hard to argue against including this combination along with Zytiga, Erleada or docetaxel. However, the use of Zometa when one is still hormone-sensitive is controversial. An argument can be made for putting it off until there is evidence of osteoporosis on a DEXA scan - the risk of the worst side effect- osteonecrosis of the jaw - increases with the amount of time taking it.

The hormonal therapies have different modes of action, but without a randomized clinical trial, it's impossible to say that one extends life more than the others. Xtandi and Zytiga are being compared in an ongoing arm of STAMPEDE. (Zytiga prevents the formation of androgens by the adrenal glands and via intra-tumoral synthesis. A recent study suggests that it stops formation of testosterone by the testicles as well. Xtandi and Erleada block the androgen receptor and prevents its translocation into the nucleus, where it can invigorate the cancer even without outside androgens. Erleada also prevents "upgrading" of the androgen receptor - a mode of castration resistance where multiple copies of the androgen receptor appear on the cancer cell, so it can be activated by even the slightest amount of androgen. However, it is unknown whether it slows down castration resistance in clinical practice - the cancer cell evolves many workarounds. A small trial and STAMPEDE found that combining Zytiga and Xtandi did not improve survival in the castration-resistant setting, but side effects were worse. 

Because neither docetaxel nor Zytiga showed a clear survival advantage when men were randomized to one or the other (Sydes et al.), the decision must be made based on other factors.

Both docetaxel and Zytiga increase toxicity over ADT alone. In the LATITUDE trial, physicians reported grade 3-5 (serious to death) events among 68% taking Zytiga vs 52% on ADT only. Higher rates of grade 3 hypertension and hyperkalemia were observed. In the STAMPEDE trial, physicians reported grade 3-5 events among 47% of those taking Zytiga vs. 33% of those taking ADT only. Higher rates of hypertension and liver enzyme elevation were observed. In the TITAN trial (Erleada), where almost two-thirds had high-volume metastases, Grade 3 (serious) and Grade 4 (life-threatening) toxicities were similar (41-42%) for those who got apalutamide or placebo. In the ENZAMET trial, serious side effects were experienced by 42% of those taking Xtandi vs 34% of those taking an early antiandrogen. The rate of serious side effects is remarkably similar.

In the docetaxel trials, STAMPEDE reported grade 3-5 events among 52% taking docetaxel vs 32% taking ADT only. Neutropenia, lethargy and GI disorders were especially elevated. CHAARTED reported grade 3-5 events among 30% taking docetaxel. Neutropenia, fatigue, gastrointestinal and allergic reactions were elevated.

Based on patient-rated global quality of life after 2 years (see this link), docetaxel and abiraterone were not meaningfully different in patients randomized to one or the other. Abiraterone was better than docetaxel at 12 weeks and 24 weeks. One might expect that the increase in toxic events would have been worse with docetaxel, but while they were different in kind, the incidence of all events requiring medical attention was similar for both treatments. All medicines seem to have lower incidence of side effects when they are used earlier, while patients are healthier.

High volume/low volume of metastases

Planned subgroup analyses of both CHAARTED and STAMPEDE showed that certain different therapies may improve survival depending on the number of distant metastases found using a bone scan/CT. Remember that high volume was arbitrarily defined as visceral metastases or 4 or more bone mets with at least one beyond the pelvis or vertebrae; low volume is anything less than that (often referred to as oligometastatic).

For men who are diagnosed with a low volume of metastases (oligometastatic), debulking can add to survival. STAMPEDE recruited participants before the benefit of early Zytiga was known, so it is unknown how the two therapies might interact. It is reasonable to speculate that early Zytiga may be used to radio-sensitize the cancer to debulking with radiation. The role of metastasis-directed SBRT has yet to be proven, but may be considered when safe to do so.

In a post-hoc analysis of LATITUDE data, men with high volume disease benefited from early use of Zytiga, but men with low volume disease did not. In STAMPEDE, there was no difference - Zytiga was equally effective in both groups. Erleada also seems to be equally effective in both groups. However, LATITUDE had mostly high-volume disease men in its sample. For men with a high volume of metastases, docetaxel or Zytiga (but not debulking) may confer a survival benefit). Xtandi seems to benefit most those with low volume of metastases.


Can they be combined or sequenced?

The PEACE-1 trial showed that the combination of docetaxel and Zytiga improved outcomes significantly.

A major clinical trial, ACIS, found that the combination of Erleada and Zytiga increased radiographic progression-free survival in men who were already castration-resistant. That combination improved results (in the AASUR trial) when given as an adjuvant therapy along with prostate radiation to men with very high-risk localized prostate cancer, and will be testedamong high-risk patients with high Decipher scores in the PREDICT-RT trial. The combination is being tried along with salvage radiation in men who have failed prostatectomy in the INNOVATE trial. An ongoing clinical trial is investigating whether Erleada combined with Zytiga extends survival in the relapsed hormone-sensitive setting.

There is a hint that docetaxel may have some efficacy in keeping Zytiga working longer. The androgen receptor always eventually becomes resistant to the effect of Zytiga. Sometimes resistance is attributable to a change in the androgen receptor called "the AR-V7 splice variant." There was a very small (n=14) trial at JH where they were looking at the role of the AR-V7 splice variant in resistance to second-line hormonals (Zytiga or Xtandi). In a few guys (6 out of 14) who were AR-V7 positive after that hormone therapy, they became AR-V7 negative after docetaxel treatment. This is also an effect that they were hoping that supraphysiological doses of testosterone might sometimes create (see this link).

This may work both ways. Hormonal agents may even re-sensitize the cancer to docetaxel after it has become docetaxel-resistant (see this link). It may turn out that alternating the use of chemo and advanced hormonals (and testosterone!) is a good strategy.

For logistical reasons, it may be useful to start with six cycles of docetaxel, which would take 15 weeks. In this way, Zytiga, Erleada or Xtandi can begin 15 weeks later. If one starts with Zytiga, it may take three or more years before it stops working and docetaxel can be tried (Among metastatic men, failure-free survival was about 4 years in STAMPEDE, radiographic progression-free survival was 33 months in LATITUDE). It seems that one can receive more therapies in less time if a patient begins with docetaxel.

It is possible that concomitant early use of Zytiga and docetaxel may have a synergistic effect on the cancer, and in preventing the onset of Zytiga resistance. This is pure conjecture and would have to be proved in a clinical trial. The downside is the cumulative side effects.

The other possibility is starting with docetaxel only and following up with the combination of Zytiga +ADT. By holding off on ADT use, it might delay some of the selective evolutionary pressure that leads to early Zytiga resistance. It is unknown whether early docetaxel without ADT has similar efficacy to the combination. Again, this is a good hypothesis to be tested in a clinical trial.


Will Provenge, Xofigo and Jevtana also be more beneficial if used earlier?

Isn't earlier always better? Not necessarily (see this link). Cancer is a moving target, continually altering its genetic make-up. What works when cancer is in one state may not necessarily work when cancer is in another state. There can be unpredictable interactions. Early and prolonged use of bicalutamide, for example, may actually eventually increase the cancer growth rate; yet, with cancers that have become castration-resistant, adding bicalutamide may sometimes slow it down.

Although Provenge is more effective when the patient's disease is less progressed (see this link), it was not any more effective when used for mHSPC (see this link). Xofigo is in a clinical trial for mHSPC, and Jevtana is in trials for use before docetaxel.

What about nuclear medicines?

An exciting new field is the use of nuclear medicines (alpha-emitters like Xofigo, and beta-emitters like Lu-177-PSMA). Their use has historically been restricted to men with mCRPC. There is a clinical trial of Lu-177-PSMA for men who are castration-resistant but are not yet detectably metastatic (see this link). The PSMAddition trial is for men who are newly diagnosed or metastatic with metastases. The hope is that they can seek out and destroy micrometastases that may be in systemic circulation.

What happens if they are used later?

Most of the advanced prostate cancer medicines were approved for men who were metastatic and castration-resistant (mCRPC). In that setting, docetaxel adds a median survival of 3 months (see this link), compared to a median of 17 additional months among men with high volume metastases in the CHAARTED trial. Zytiga adds 4 months to survival among men who are castration-resistant and have had chemo (see this link). Median (50%) survival was reached at the extended follow-up of the STAMPEDE trial. Median survival was 46 months in the SOC group, and 79 months in the Zytiga group. So, early Zytiga increased median survival by 33 months; In LATITUDE (in which all patients were more progressed), early Zytiga increased median survival by 16.8 months.

We might surmise that if used after metastatic diagnosis but before castration-resistance sets in, the survival improvement might be somewhere in between. However, long-term use of ADT drives changes in the androgen receptor that might shorten the time during which Zytiga is effective. Docetaxel, on the other hand, remains effective even after advanced hormonal agents have been utilized.

What are the other alternatives for metastatic hormone-sensitive prostate cancer (mHSPC)?

Supraphysiological doses of testosterone alternating with ADT (called Bipolar Androgen Therapy or BAT) has shown efficacy in some men (see this link). Expanded trials will tell us which men are most likely to benefit from it.

Treatment of the prostate even after metastases have been discovered  (called "debulking") is an intriguing prospect. However, the most recent reported arm of the STAMPEDE trial showed that prostate-only radiation only provided a survival benefit in oligometastatic men (see this link). There are clinical trials at MD Anderson and Rutgers (not recruiting), and registries at UT Southwestern and MSKCC and the Los Angeles VA that will further explore this opportunity. Princess Margaret Hospital in Toronto is using SBRT for this purpose (see this link). Other trials are ongoing in Europe (this one includes docetaxel and Zytiga): Ghent, and Hamburg.

Other early-use therapies are combined with ADT in clinical trials. These trials are still active:

• apalutamide + Zytiga + debulking (RP or RT). (first results expected Feb 2024)
• Johns Hopkins is testing a PARP inhibitor for potential use instead of ADT in men with germline DNA repair defects(first results expected Dec 2023)
• enzalutamide ± Keytruda  (first results expected in  July 2026)

Is prostate-specific radiation still of any value in men diagnosed with distant metastases? Redux

Sometimes called “cytoreductive treatment” or “debulking,” removal of the primary cancer has been used effectively in other cancers, using either radiation or surgery to increase cancer-specific survival time. In the previous post (see this link), we looked at the evidence for “closing the barn door after the horses are out.” The bottom line was a highly qualified maybe.

Rusthoven et al. probed the National Cancer Database (NCDB) for patients who were newly diagnosed with metastatic prostate cancer between 2004 and 2012. The dataset included:

• ·      6382 men with metastatic prostate cancer, all treated with androgen deprivation therapy (ADT).
• ·      538 of them also received prostate radiation (RT) following diagnosis.
• ·      Some had prostatectomy rather than radiation.
• ·      There was complete information on PSA, Gleason scores and comorbidities.
• ·      In addition, age, year, race, clinical stage, lymph node stage, chemotherapy treatment, treating facility and insurance status were used in multivariate analysis.

At a median follow-up of 5.1 years, and after compensating for all the above-mentioned variables:

• ·      Overall survival was 38 percent greater among those who had RT.
• ·      Median overall survival was 55 months among those who had RT, 37 months among those who didn’t.
• ·      5-year overall survival was 49 percent with RT, 33 percent without it.
• ·      RT was associated with greater overall survival among those who survived at least 1 year, at least 3 years, and at least 5 years.
• ·      Survival was similar for RT and prostatectomy.

Based on what we’ve learned about early use of docetaxel and androgen deprivation therapy (ADT) from the CHAARTED and STAMPEDE studies, chemo+ADT has become the standard of care. However, during the time period examined by this study, early chemotherapy was not often used. While the authors looked at chemotherapy use, it was most probably the treatment of last resort in the most progressed cases. Therefore, whether RT or surgery is of any benefit after early use of chemotherapy is still very much an open question.

This database analysis makes a compelling case for conducting a prospective randomized trial for early use of radical radiation therapy when metastases have been detected at the time of diagnosis. The radiation would include the whole pelvic area with spot treatment of distant metastases. Because the optimal sequencing of RT and chemo is unknown, this would have to be a 2X2 design. That means there would be 4 arms: one with chemo followed by radiation, one with chemo only, one with radiation followed by chemo, and one with radiation only. Because few patients in the US are initially diagnosed with metastases, this would have to be a multi-centered trial, or perhaps a European trial. What is unclear is who will undertake such a study and how will it be financed.

While waiting for that trial (and it will probably be a long time before we have any outcomes, even if one were already begun), the patient diagnosed at the outset with metastases should initiate this conversation with a radiation oncologist. As we saw in the earlier commentary, the answer continues to be maybe, but with somewhat more justification for considering such treatment.

Update (3/29/17):

Parikh et al. reported a similar National Cancer Database analysis on 6,051 newly diagnosed metastatic patients treated between 2004 and 2013. 622 received local therapy, 52 RP. Men who received local therapy were: 

• younger
• had fewer comorbidities
• lower T stage
• Gleason score <8
• Negative lymph  nodes

Five-year overall survival was 47% among those who received local therapy, 17% among those who did not. The difference remained significant after an attempt was made to correct for patient risk characteristics.

Update (3/3/18):

Dall'Era et al. reported on their analysis of the database from the CDC Breast and Prostate Cancer Data Quality and Patterns of Care Study. They looked at 9-year prostate cancer-specific survival of men with either locally advanced or metastatic prostate cancer. After correcting for patient risk characteristics, they found that prostate-directed treatment (radiation or surgery) was only associated with increased survival among those with locally advanced prostate cancer, but not among those with metastatic prostate cancer.

While this is another encouraging retrospective analysis, it is subject to selection bias - the men who received local therapy had fewer risk characteristics. It is worth noting that a similar thing had occurred with breast cancer. Several retrospective studies had suggested that resection of the breast tumor  plus axillary lymph nodes increased survival even when distant metastases were detected. However, Badwe et al. reported that when women were prospectively randomized to that treatment or no such treatment, there was no survival difference. Only a randomized clinical trial like this one  at MD Anderson, or this one in Canada, or these others in Europe (ISRCTN06890529,  NCT02454543, NCT01957436, NCT00268476) can decide this issue for prostate cancer. Until we have those results, patients have to weigh that uncertainty against the very serious adverse effects of radical treatment, especially of surgery where it is likely that the prostate tumor penetrance will be extensive, and where extensive pelvic lymph node dissection may result in lymphedema and lymphocele.

Is prostate radiation still of any value when diagnosed with distant metastases?

In some cancers, debulking the tumor, also called cytoreduction, either with radiation or surgery, has been found to slow progression. Is that true of prostate cancer? In theory, removing the prostate from the metastatic equation may have any of several benefits:

• ·      It reduces the cancer cell load available to spawn new metastases.
• ·      The original cancer in the prostate may be especially able to signal the creation of a bone environment conducive to metastases.
• ·      Castrate resistance may set in earlier in the original tumor, and those resistant cells may metastasize.
• ·      The abscopal effect: radiation-destroyed cancer cells present antigens to the immune system.

But there is a contrary hypothesis as well; i.e., that removing the initial tumor actually accelerates the metastatic process. Under this hypothesis, the original prostate tumor suppresses certain growth factors and angiogenesis factors, which keeps the cancer dormant. There are also concerns that surgical debulking may release viable cancer cells into systemic circulation (see this commentary).

Cho et al. looked at the records of men treated from 2003 to 2011 at the Yonsei Cancer Center in Seoul, South Korea who were originally diagnosed with distant metastases. In all, they found 38 men who had external beam cytoreductive prostate radiotherapy (PRT), and all of them had palliative radiation of distant metastases as well. Their “control group” comprised 102 men, 39 of whom had palliative radiation of metastases, but not of the prostate. Almost all had androgen deprivation therapy.

The authors point out that the only patient characteristic that was significantly different between the two groups was age. 71 percent of the group that received prostate radiation was under 70, but only 49 percent of the controls. It is worth noting that although the differences weren’t statistically significant on this small sample size, there was a consistent pattern. Those who received prostate radiation were not only younger, but had better performance status, lower initial PSA, more likely to have just one metastasis and less likely to have more than five, and were less likely to have visceral metastases. So it is possible that the PRT group had the better survival prognosis regardless of whether they got the prostate radiation.

After a median of 34 months of follow-up, the following statistically significant differences in outcomes were reported:

• ·      Median PSA nadir: 0.61 ng/ml for PRT group, 1.12 ng/ml for controls
• ·      Percent achieving a PSA nadir <4 ng/ml: 87 percent for PRT group, 55 percent for controls
• ·      3-year overall survival: 69 percent for PRT, 43 percent for controls
• ·      3-year biochemical failure free survival: 52 percent for PRT, 16 percent for controls

Within the control group, the differences in outcomes were not statistically significant between the 39 patients who received palliative radiation and the 63 patients who had no radiation at all.

There was no severe urinary or rectal toxicity. However, there were some severe cases of leukocyte and platelet depression because of the palliative treatment of bone metastases.

Although performance status, as well as number and kind of metastases were correlated with overall survival, on multivariate analysis, only PRT was significantly correlated.

On the surface, there seems to be a case for cytoreductive prostate radiation here, but caution is warranted. The PRT group had consistently better numbers from the start. It seems likely that they received PRT because of their better outlook. This kind of selection bias seems to be driving the results. We see it especially in the multivariate analysis: the factors like age, performance status and number and kind of metastases are already subsumed into the selection of PRT patients, so they do not appear to be independently significant. This is also too small a sample size to be able to make any real judgments. For that, we will have to wait for some future randomized clinical trial.

There have been a few other such studies. Culp et al., in their analysis of the SEER database, found that metastatic men who had their prostates removed or treated with brachytherapy had longer prostate-specific survival than those who had no de-bulking. Their analysis did not account for the extent of bone metastases, whether pelvic lymph node dissection was performed, or whether they received systemic treatment (ADT or chemo), and the same selection bias may be at work as in the Cho study.

Antwi and Everson performed a similar SEER database search, this time adjusting for socio-demographic factors and tumor attributes, and found that prostatectomy in metastatic men was associated with a 72 percent reduction prostate cancer-specific mortality; brachytherapy was associated with a 54 percent reduction. Fossati et al. also looked at the SEER database and found that there was a subset, those with prostate cancer-specific 3-year mortality risk of less than 40 percent, who benefited from cytoreductive therapy.

The closest we have to a randomized clinical trial was a pilot case-controlled prospective study, reported by Heidenreich et al., of 23 men with 1-3 bone metastases, no visceral metastases, non-extensive lymph node involvement, who were all hormone responsive and were treated with prostatectomy. This was compared to a case-control group of 38 men with metastatic prostate cancer who only received hormone therapy. The prostatectomy group had longer time to castration resistance (40 months vs. 29 months), longer progression-free survival (39 months vs. 27 months), and longer prostate cancer-specific survival (96 percent vs. 84 percent with median 3-4 years of follow-up). The overall survival was similar.

We are left with intriguing hints, but no reliable data. Surgical de-bulking carries risk of incontinence and almost certain impotence, considering nerve-bundle preservation would be unlikely. Radiation carries less urinary and sexual risk, but is not risk free. If it is beneficial at all, full pelvic radiation would probably be optimal for slowing cancer progression. The use of SBRT and multi-modal therapies, like brachytherapy boost and adjuvant ADT, have yet to be explored.

Unfortunately, there seem to be few clinical trials, although clinicians are doing this selectively with some patients. There is a randomized clinical trial at MD Anderson (NCT03678025). A registry in Dallas (NCT02170181) includes metastatic patients treated with SBRT prior to chemotherapy. Rutgers Cancer Institute in NJ has a clinical trial (NCT03456843) of surgical de-bulking. The Los Angeles VA is combining prostatectomy, metastasis-directed SBRT and 6 months of advanced hormone therapy (Lupron, Zytiga and apalutamide) for newly diagnosed patients with 1-5 metastases.