Thursday, August 25, 2016

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.

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