Thursday, August 25, 2016

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.

No comments:

Post a Comment