Unwarranted conclusions about oligometastatic treatment

Some patients wonder, if they just have a couple of metastases, why can't those be "zapped" by a few quick SBRT treatments and thereby be cured of their prostate cancer? Or, even if they can't be cured, can't the cancer's progression be slowed down?

To address those questions, we have to understand what is called the "natural history" of prostate cancer progression. Even high-risk prostate cancer is quite a different sort of thing from metastatic prostate cancer. High-risk prostate cancer cells, for example those with Gleason score 5+5, are incapable of thriving outside the prostatic environment. At some point they undergo a genetic transition called epithelial-to-mesenchymal transition (EMT), after which they can freely move throughout the body in the lymph, blood or the spaces around nerves, and plant themselves and accumulate in distant locations. Sometimes those microscopic metastases can circulate for a long time before planting themselves somewhere new. Sometimes they can plant themselves but do not proliferate appreciably for a long time. Sometimes they can alter the tissue environment in a new place (especially bone tissue) so it is more amenable to clumping and proliferation. Sometimes those cells get caught in lymph nodes (lymph nodes may be thought of as filters to catch cellular debris, including cancer cells) and proliferate there. All of these processes occur simultaneously.

Let's try to gain an understanding of how many cancer cells are in systemic circulation at a given time. We have found that a count of 5 or more circulating tumor cells (CTC) per 7.5 ml of blood is associated with metastatic progression (the prostate is also always shedding cells, healthy and cancerous, that are not capable of metastatic progression). So a 200 lb. man with no detectable metastases and with a CTC count of 5, who has 6.5 liters of blood, will have at least 4,300 circulating tumor cells. In addition, there will be many thousands more lodged in and between tissues. Now, to be detectably metastatic with today's best imaging technology, a clump of tumor cells must be at least 4 mm long. The cancer cell may be about 10 μm, so there are at least 200,000,000 of them before the smallest metastasis becomes detectable. All of those cancer cells are constantly shedding and forming new daughter metastases elsewhere. So cancer cells may be circulating, clumping, and growing for a long time before they form a big enough clump to be detectable.

It should be clear that there is no possibility of a cure without systemic treatment. Currently, we have no systemic treatments that can cure metastatic prostate cancer.

How long does it take to go from the first microscopic metastasis to the point where it is detectably metastatic? That's impossible to know with any accuracy for a given individual. What we do know is that on average it takes 8 years from the time a man is biochemically recurrent after prostatectomy to the time when the first bone metastases are detected on a bone scan (see this link). That represents the accumulation of perhaps a billion cells in one place. It may be years more before the next bone metastasis is detected. Lymph node metastases are the slowest progressing of all the kinds that prostate cancer causes. It is not unusual for many years to pass between new detectable lymph node metastases. The new PET scans detect metastases much earlier, when the tumors are 80% smaller.

Now we can come back to the question of whether early detection and treatment of metastases can at least slow progression and increase survival. A C-11 Choline PET/CT may be able to reliably detect metastases when the PSA is only about 2 ng/ml, rather than 20 ng/ml for a bone scan. The newer PSMA-based PET/CTs may detect metastases even earlier, say at about 0.5 ng/ml. So, if any treatment is given when metastases are detected this early, and then we find that it takes a very long time - many years - to detect subsequent metastases, did the treatment delay progression? This effect is called "lead-time bias."

Adding to the confusion is the fact that those big clumps of detectable cancer cells are the source of much of the PSA. When those detected metastases are "zapped," the cancer cells in them no longer secrete PSA and the cancer is controlled locally. We also know that old clumps of cancer are a rich source for new tumor cells. Is it possible that reducing at least that local source of metastatic cells will slow progression?

The only way to answer this question with any assurance is to conduct a randomized clinical trial. Some patients will get the treatment, in this case SBRT to the detected metastases, and the other patients will get standard of care -- hormone therapy. Then we will be able to see how long it takes for new distant metastases to be detected for the treated group as compared to the control group; and more importantly, did the treated group survive longer?

Triggiani et al. retrospectively report on patients at several centers in Italy (for some reason, most of these studies have been done in Italy) who had 3 or fewer detected metastases treated with SBRT.

• About 100 patients with a recurrence after primary treatment with metastases detected by Choline PET scan (the oligo-recurrent group)
• 41 castration-resistant patients with metastases detected by bone scan/CT (the oligo-CRPC group)

After a median of 20-23 months of follow-up, distant progression-free survival was:

• 43% after 2 years for the oligo-recurrent group
• 22% after 2 years for the oligo-CRPC group

The authors conclude:

"Stereotactic body radiotherapy seems to be a useful treatment both for oligo-recurrent and oligo-CRPC."

We are now ready to understand why this is an unwarranted conclusion. There is no way to know, based on the data they provided, whether the treatment was "useful" or not. We have no way of knowing what the distant progression-free survival would have been had they not received the SBRT treatment. Inexplicably, several groups from Italy also reached such unwarranted conclusions.

In fact, in a meta-analysis with longer-running follow-up data, Ost et al. (commented on here) found that for oligo-recurrent patients, distant progression-free survival was:

• 31% after 3 years, and only
• 15% after 5 years

In other words, the vast majority (85%) of men with SBRT-treated oligometastatic recurrence had detectably relapsed within 5 years. Given the lead-time bias and the slow rate of detectable early progression anyway, it is impossible to say that the radiation treatment accomplished anything. Until we have some proof, patients should approach metastatic treatment for anything but palliative purposes with caution. There is currently no evidence, none, that treatment of metastases has any effect on survival.

In spite of the lack of evidence, if a radiation oncologist looking at the patient's anatomy finds metastatic radiation to be safe, then there is little reason other than cost to abstain from it. However, a patient is taking a survival risk if he puts off hormone therapy in order to find metastases, especially in light of early evidence from the TOAD study.

Treatment of pelvic lymph nodes is a special case. If a patient is able to detect any metastatic pelvic lymph nodes, and he is convinced that he should have treatment at all, he should consider treatment of the entire pelvic lymph node field rather than isolated pelvic lymph nodes. One has to treat what one can't see as well as what one can see; again, provided that it is safe to do so. Safety may be questionable because of anatomy, lack of visceral fat, history of bowel inflammation, and previous pelvic radiation. The evidence for efficacy is mixed. Some retrospective data analyses (Rusthoven, Abdollah, Jegadeesh) found a survival benefit, while some did not (Kaplan and Johnstone). These retrospective studies are notoriously confounded by selection bias (i.e., the patients who got the therapy were the most likely to improve anyway). We await the outcomes of the randomized clinical trials before we have a more definitive answer.

There are currently several randomized clinical trials that have begun. Few are large enough or scheduled to run long enough to detect a survival benefit for prostate cancer. So far, the trials are in London, Montreal, France, Ghent, Italy and at Johns Hopkins.

Metastases after early vs. delayed salvage radiation

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

Den et al. posted the outcomes of their investigative analysis at the ASCO Genitourinary Conference (Abstract 12). Data on 422 patients treated at 4 institutions were retrospectively analyzed. All had adverse pathology (either stage T3 or positive margins) after RP. Patients were arbitrarily divided according to their PSA after surgery at the time they received radiation:

• ·      <0.2 ng/ml – “adjuvant RT” (111 patients)
• ·      >0.2 but <0.5 ng/ml – “early salvage RT” (70 patients)
• ·      >0.5 ng/ml – “delayed salvage RT” (83 patients)
• ·      No radiation received (157 patients)

CAPRA-S scores and Decipher genomic classifier scores were found to independently predict risk of metastatic progression. Adjusting for those scores:

• ·      Delayed salvage RT increased risk of metastases by 4.3 times over adjuvant RT
• ·      No radiation increased risk of metastases by 5.4 times over adjuvant RT
• ·      Early salvage and adjuvant RT had about the same risk of metastases
• ·      Men with low CAPRA-S and Decipher scores had low risk of metastases
• ·      Men with high CAPRA-S and Decipher scores benefit from adjuvant RT, but had high rates of metastases nonetheless.

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

Risk factors for primary radiation failure and timing of progression

Zumsteg et al. searched the database at Memorial Sloan Kettering Cancer Center (MSKCC) to determine the risk factors associated with cancer progression after primary radiation treatment, and the timing of progression. Their retrospective analysis looked at records of 2,694 patients treated at MSKCC with radiation doses between 76 Gy to 86 Gy. The median follow-up was 83 months for all patients and 122 months for those who experienced biochemical failure (defined as nadir+2). They did not report what, if any, salvage treatment was used. The researchers found:

• ·      23% of patients experienced biochemical failure.
• ·      The median time from biochemical failure to detection of distant metastases was 5.4 years.
• ·      The median time from biochemical failure to prostate cancer-specific mortality was 10.5 years, 5.1 years after metastases were detected.
• ·      Risk of clinical progression following biochemical failure were independently associated with:

o   Shorter PSA doubling time

o   Higher clinical stage

o   Higher Gleason score

o   Shorter time to biochemical failure

John Hopkins reported that for men treated with surgery, 19% experienced biochemical failure. Some of the difference may be attributable to the inadequate dose of radiation (76 Gy) used on some patients, or that those patients were diagnosed with more aggressive disease. The median time from biochemical recurrence to detection of distant metastases was 8 years, 3 years among those who did not have salvage radiation after biochemical recurrence (Antonarakis et al.), The shorter time in the radiation study may reflect the fact that patients choosing radiation have historically been older and further progressed at time of diagnosis. The median time to death after metastases were detected was 5 years – identical in both studies. They all report the same risk factors for clinical progression.

The numbers reported for initial radiation therapy are similar, at first blush, to those reported for initial prostatectomy. Because there will probably never be a randomized clinical trial of surgery vs. radiation, it is tempting for the patient faced with the choice of initial therapy after diagnosis to compare these datasets, both from top institutions in their respective specialty. While I would very much like to see the patient characteristics and the data stratified by risk group and salvage treatment, if any, there does seem to be a similar overall pattern. Some patients will have already experienced undetected micrometastases before treatment, and they will not be cured by either therapy using current methods. Other patients, most in fact, will be cured by either therapy.

Genomic classifier can help identify patients who may not need adjuvant radiation.

A decision that tortures patients with adverse findings (positive margins, and/or stage T3/4) after prostatectomy is whether to jump into adjuvant radiation right away, or wait until PSA rises to 0.2 ng/ml before having salvage radiation. We want early treatment while the cancer is still local, but we don’t want to over-treat cancers that may never require treatment in one’s lifetime. Currently, only about 10% of post-prostatectomy patients with adverse pathology are getting adjuvant radiation. In a recent article, I noted that PSA, Gleason score, and stage may not adequately capture the risk of progression. Radiation oncologists commonly rely on tools like the CAPRA-S score or the Stephenson nomogram to predict the outcome of salvage radiation.

Karnes et al. in a study at the Mayo Clinic in 2013 retrospectively looked at the genomes of prostatectomy patients with adverse findings to see if they could predict whether they would progress to metastasis. Metastatic progression is used as a surrogate endpoint for prostate cancer mortality because of the very long natural history of progression. Even progression to metastases takes a very long time – 8 years median among those who progress. The researchers only followed the patient case files for up to five years, so we expect to see proportionately fewer metastatic cases. They found that a genomic classifier (GC), Decipher ™, could reliably predict those patients with adverse pathology after RP that would go on to develop metastases.

They performed GC analysis on tissue samples from a random sample of 256 patients who were at high risk of recurrence owing to any of several factors: PSA>20 ng/ml, GS≥8, pT3 or positive margins. They augmented the sample to include 73 patients who were known to eventually progress to metastases. They tracked whether patients progressed to metastasis within 5 years. Median time to metastases was 3.1 years. The researchers found that:

·      GC had a predictive accuracy of .79, which was significantly better than any of the clinicopathological risk factors or the Stephenson nomogram.

·      Independent of all other risk factors, every 10% increase in GC raised the risk of metastases by 58%.

·      60% had a GC score <0.4. They had a 5-yr cumulative incidence of metastases of only 2.4%.

·      20% had a GC score > 0.6. They had a 5-yr cumulative incidence of metastases of 22.5%.

·      While there was some correlation between Gleason score and GC score, 36% of those with GS≥8, had low GC scores and 77% of that subset remained metastasis-free.

Researchers at Thomas Jefferson University and the Mayo Clinic (Den et al.) performed a similar study, but they only looked at the cases of patients who had adjuvant or salvage radiation after RP. Because the patients had both RP and RT, we expect that the cytoreduction would slow down the rate of metastases, if not prevent them, if they weren’t already micrometastatic. The 188 patients in their study had positive margins or stage pT3, and were all treated with radiation after RP between 1990 and 2009. Their cases were analyzed for up to 5 years following RP.

They used the genomic classifier (GC) on prostatectomy tissue samples to classify them as low, average, and high GC scores. GC scores range from 0 to 1. Based on the Karnes et al. study, they classified low scores as 0-0.4, average scores as 0.4-0.6, and high scores as 0.6-1.  The researchers found:

·      Of all the risk factors comprising GC, CAPRA-S score, age, preoperative PSA, Gleason score, stage, surgical margins, time between RP and RT, and whether adjuvant or salvage RT was given, only three were helpful in predicting metastatic progression: GC, preoperative PSA, adjuvant RT, and CAPRA-S score. Of those, GC was the strongest predictor. Independent of all other risk factors, every 0.1 increase in GC raised the risk of metastases by 66%.

·      5-year rates of metastasis were:

o   0% in those with low GC score

o   9% in those with average GC score

o   29% in those with high GC score

·      In patients with GC score less than 0.4, there was no difference in incidence of metastases whether they received adjuvant or salvage radiation.

·      In patients with GC scores at or greater than 0.4, the 5-year cumulative incidence of metastases was:

o   6% if they received adjuvant radiation

o   23% if they received salvage radiation

·      The “survival concordance index,” a measure of how accurate a tool is for predicting survival (or in this case, metastases), was much greater for GC (0.83) than for the CAPRA-S score (0.66) or the Stephenson nomogram (0.67).

This study suggests that adjuvant radiation may be beneficial if the patient has a high GC score, while those with a low GC score can comfortably wait for salvage radiation.

In this study, all the tissue samples were from patients who went on to receive adjuvant or salvage radiation. What happens to patients who decide not to have radiation after RP?

One such study by Ross et al. of Johns Hopkins of the genomic classifier was presented at the 2015 Genitourinary Cancers Symposium. The sample of patients they studied had the following characteristics:

·      260 patients

·      Intermediate or high risk treated with surgery between 1992 and 2010

·      Undetectable PSA after surgery

·      No therapy prior to detected metastases

·      77% were stage pT3a, 28% were stage pT3b, 28% had positive margins, 20% were N(1), 36% were GS≥8

·      By 15 years, 38% had biochemical recurrence, 21% had metastases, and 9% died of prostate cancer.

·      Median GC score was .47 among those who had metastases, and .28 among those who didn’t.

·      The risk of metastases increased by 48% for every 10% increase in GC Score.

·      GC Score predicted metastases independent of other clinical risk factors.

Most men (79%) did not go on to have metastases, even after 15 years and even with no salvage radiation, again raising the issue of potential over-treatment if they had received adjuvant or salvage radiation. Clearly, we need a tool to help us better predict risk of metastatic progression.

Another small study by Klein et al. at the Cleveland Clinic looked at patients who did develop metastases within 5 years of surgery, and who had no adjuvant or salvage radiation. They found 15 such patients, called “rapid metastases,” who had been treated between 1987 and 2008. These were compared to 154 control patients who did not develop rapid metastases. The controls were nevertheless at very high risk for developing metastases; they were screened for the following characteristics:

·      Preoperative PSA>20 or stage pT3 or positive margin or GS≥8, and

·      N(0), and

·      Undetectable post-RP PSA, and

·      No neoadjuvant or adjuvant therapy, and

·      Minimum 5 years of follow up

The researchers found that GC could distinguish those who developed rapid metastases from those who did not, with an odds ratio of 1.48. They also found that GC was a better predictor than the CAPRA-S score or the Stephenson nomogram.

These studies corroborate a similar finding by Feng et al. in an earlier study. They found that among patients with biochemical progression (PSA≥0.2 ng/ml), GC was a better predictor of metastatic progression than other clinical or pathologic risk factors. 40% of those with high GC scores developed metastases within 3 years of biochemical recurrence, compared to only 8% among those with low GC scores.

Genome Dx wrote that the positive predictive value (PPV) of a GC score greater than 0.4 was 69 percent in the Karnes validation study. This means that more than two-thirds of the time, it correctly (albeit retrospectively) predicted those men who went on to suffer metastases. Conversely, it means that about a third of men with high scores might be over-treated, at least with 5 years of follow-up, if they relied on a high GC score to make their salvage treatment decision. Complicating the interpretation is the fact that the natural history of progression is quite long, and may be further delayed by the debulking of the tumor burden from the initial prostatectomy. So longer follow-up, say, 10 or 15 years, might reveal that it predicted progression better.

The negative predictive value (NPV) of 98.5% for a GC score < 0.4 is particularly impressive. However, we still have the problem of the long natural history of progression. While a GC score under 0.4 almost certainly rules out risk of metastatic progression in the next 5 years, we don't know how safe we are in a 10- or 15-year time frame.

Even with these uncertainties, it is a better decision tool than our other available alternatives.

All of the above studies were retrospective, but I am doubtful that a prospective study will be undertaken because of the very long time needed to obtain sufficient metastatic cases.

Cumulatively, these studies build a good case that Decipher™ can do a reasonably good job of discerning which patients with adverse postoperative pathology but undetectable PSA could reasonably forego adjuvant and salvage radiation. It seems to be less accurate at predicting which patients would require radiation to prevent metastases, although it is a better predictor than other tools we have at our disposal. I was hoping Genome Dx would supply the sensitivity, specificity, and positive and negative predictive value at various cut-offs, but they did not respond to my request.

At $4,000+ this is an expensive test. However, considering that a course of adjuvant or salvage radiation can cost over $30,000, and the potentially worse side effects associated with adjuvant radiation, this test seems to have a reasonable cost/benefit ratio. It is covered by Medicare, many private insurance providers, and there is a financial assistance program available.

This is a difficult decision even with a GC score in hand, and one that should only be made in a shared decision-making process between patient and doctor.

note: Thanks to Dr. Robert B. Den for allowing me to see the full text.

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.

First in-human trial of Actinium-225-PSMA-617

Among the more interesting developments in radiation oncology/nuclear medicine in recent years are novel therapies created by attaching radioactive isotopes to molecules (called ligands) that attach to the prostate-specific membrane antigen (PSMA) that is found on the surface of most metastatic prostate cancer cells.

We have seen several small studies conducted throughout Germany using Lu-177-PSMA (see this link for latest update).  Lu-177 is a beta (β) particle emitter – its radioactivity is produced when a neutron decays into a proton and an energetic electron – a beta particle. Xofigo is an alpha (α) particle emitter – its radioactivity occurs when the radium 223 nucleus releases 2 protons and 2 neutrons – an alpha particle or helium nucleus. There are advantages and disadvantages to each (see table in this link).

Lu-177-PSMA was developed at the University of Heidelberg. Those researchers have developed a targeted therapy using an alpha emitter called actinium 225. Ac-225-PSMA-617 can potentially be used in some situations where Xofigo or Lu-177-PSMA cannot. Xofigo only treats bone metastases because radium is biologically similar to calcium and replaces it in areas of active bone growth, like metastases. Ac-225-PSMA-617 has several theoretical advantages:

• ·      It can target metastases in any tissue or fluid, including undetectable, systemic micrometastases.
• ·      Because its alpha particles are very short range, it doesn’t destroy very much healthy bone marrow.
• ·      Because the alpha particles are highly energetic, they destroy nearby cells very effectively.
• ·      Because it attaches to PSMA instead of calcium-active sites in bone or other tissue, it may be less toxic to other healthy tissue.

Kratochwil et al. report a proof-of-concept in two patients treated with Ac-225-PSMA-617. They used Ga-68-PSMA-11, which shows up on a PET scan, to detect metastases that were positive for PSMA and to detect response to the alpha- emitter. The two patients selected had progressed under other treatments and were in “highly challenging clinical situations,” which included tumor infiltration into the red bone marrow. After bi-monthly treatments, both patients:

• ·      Exhibited complete PSA response, becoming undetectable
• ·      Exhibited complete tumor response on PET imaging
• ·      Exhibited no hematological toxicity; that is, no bone marrow suppression
• ·      Exhibited dry mouth from decreased saliva (xerostomia)

This is a first-in-human trial, and larger trials will be needed to prove efficacy and safety. However, it is an early encouraging development worth taking note of.