Wednesday, August 24, 2016

How early salvage radiation therapy can be used to prevent metastases and save lives

While several clinical trials have established that adjuvant radiation reduces the risk of biochemical recurrence, but only one looked at and demonstrated an improvement in metastasis-free survival and prostate cancer-specific survival. That one (see this link), only compared adjuvant radiation to “wait-and-see,” and a third of the men with a biochemical recurrence were never given salvage radiation. Some retrospective studies (see this link and this link) suggested that salvage radiation could improve metastasis-free and prostate cancer-specific survival, particularly if begun within 2 years of biochemical recurrence and when PSA doubling time (PSADT) is long.

Stish et al. examined the records of 1,106 patients who received salvage radiation therapy (SRT) at the Mayo Clinics between 1987 and 2013. They wanted to determine whether, with a large enough sample size and long enough follow-up, they could show patient characteristics and treatment variables that are associated with salvage radiation saving lives and increasing metastasis-free survival. With a median of 9 years of follow-up, they found that:
  • ·      64 percent had a second biochemical recurrence within 10 years after SRT
o   Biochemical recurrence was higher among men with higher stage, positive lymph nodes, higher Gleason scores, and shorter PSADTs prior to SRT.
o   Biochemical recurrence was lower among men with longer time to reach detectable PSA, those who had adjuvant androgen deprivation therapy (ADT) for more than a year, those who had an SRT dose ≥ 68 Gy, and those who received SRT since 2008.
  • ·      20 percent had distant metastases within 10 years after SRT
o   Incidence of distant metastases was higher among men with higher stage, positive lymph nodes, higher Gleason scores, and shorter PSADT prior to SRT.
  • ·      10 percent died of prostate cancer within 10 years after SRT
o   Prostate cancer mortality was higher among men with higher stage, higher Gleason scores, and shorter PSADT prior to SRT.
  • ·      23 percent died of all causes within 10 years after SRT
o   All-cause mortality was higher among men who were older, and those with higher stage, higher Gleason scores, and shorter PSADT prior to SRT.

As we’ve seen in so many radiation studies, adequate radiation dose (of about 70 Gy) and long-term ADT (see this link) are important for success of SRT. Outcomes are better when patients are treated when the disease has had less time to progress.

Now that use of SRT is declining, it is particularly important to show which patient and treatment variables may aid SRT in saving lives. Although current AUA/ASTRO guidelines advocate adjuvant and salvage RT, we have seen (see this link) that utilization is declining among men with adverse pathology after prostatectomy.

The authors performed a secondary analysis to determine whether it is safe to wait for a higher PSA prior to SRT. It is not. They arbitrarily used a cut-off of 0.5 ng/ml. Post-SRT biochemical recurrence, distant metastases, and prostate cancer mortality were all worse among those who did not receive SRT until PSA was over 0.5 ng/ml.

It’s important not to misinterpret this to mean that a patient can wait for his PSA to rise to 0.5 ng/ml before opting for SRT. This cut-off was chosen quite arbitrarily. Many patients were not diagnosed with a recurrence at lower PSA levels (this analysis includes patients treated as early as 1987), and ultrasensitive PSA did not become widely available until the 21st century. The authors clearly state,

This observation suggests that SRT at the lowest PSA level is most beneficial for long-term therapeutic efficacy.

Dr. Stish emphasized this point in a note to me:

We chose a PSA cutoff of 0.5 ng/ml to allow comparison with other previously reported studies that have cited this arbitrary point of dichotomy. As you read the paper, you will note that our data suggest salvage radiotherapy is most efficacious when the PSA is lowest, and in general we advocate for SRT to be considered at the earliest detectable values following prostatectomy.

As we have seen in several analyses, early SRT should be considered when the ultrasensitive PSA reaches 0.03 ng/ml (see this link). But “considered” doesn’t mean “chosen.” What is of critical importance is that the patient begin meeting with a radiation oncologist to discuss the many considerations, including positive surgical margins -- their size and Gleason score, stage T3/4, lymph node status, PSA stability, Decipher scores, and possible advanced PET studies to detect distant metastases. If they mutually determine that SRT is appropriate, discussions should include such variables as dose, hypofractionation (if any), pelvic lymph node treatment (if any), and adjuvant ADT type and duration.

 note: Thanks to Dr. Brad Stish for allowing me to review the full text and for answering questions.

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