New study: adjuvant radiation therapy saves lives vs. salvage


A major new study adds to several other studies that show that, for men with adverse pathology, adjuvant radiation (ART) within 3 to 6 months of prostatectomy saves more lives compared to waiting until the PSA rises into the range of 0.1 to 0.5 ng/ml — salvage radiation (SRT).

Three previous randomized clinical trials have shown an advantage to adjuvant radiation over a “wait-and-see” approach. However, only one of them (SWOG S8794) showed that there was an improvement in freedom from metastases and overall survival attributable to earlier treatment. That study was limited in its generalizability because only a third of the “wait-and-see” cohort ever received salvage radiation. ARO-96-02 was designed to detect differences in progression-free survival (which were significant), but it was under-powered to detect overall survival differences. EORTC 22911 was designed to detect differences in progression-free survival (which were significant), but although it had a larger sample size, overall survival did not improve. Sub-group analysis showed the survival benefit was limited to men under the age of 70. A recent meta-analysis of the three trials showed that freedom from biochemical failure, freedom from life-long ADT, and freedom from distant metastases were significantly improved by adjuvant treatment. But less than half of the men in the wait-and-see arms ever received salvage radiation, and 20 to 40 percent of them never suffered a recurrence. All three trials used salvage radiation doses that would now be deemed too low. ART utilization rates are at an all-time low of 17 percent in men with adverse pathology.

What we really want to know is this: what is the downside of waiting until the PSA rises to some arbitrary level, say 0.2 ng/ml? That is the subject of three randomized clinical trials, but we will not have the findings for several years. Meanwhile, some researchers looked at historical data in a new way to determine whether there is any evidence that might aid in decision-making.

Hwang et al. have pooled the databases from 10 top institutions: Massachusetts General Hospital, the Cleveland Clinic, the University of Michigan, Duke University, Washington University, the Mayo Clinic, the University of Chicago, the University of Miami, Virginia Commonwealth University, and Thomas Jefferson University. There were 1,566 patients who were treated between 1987 and 2013. Patients either had fully contained prostate cancer (T2) with a positive margin or extraprostatic extension (T3a) / seminal vesicle invasion (T3b) with or without a positive margin.

They used a statistical technique called “propensity score matching” that in some respects resembles what would have resulted from a prospective randomized trial. Every patient who had ART was matched, in terms of patient characteristics, to a patient who had SRT. Patients are chosen randomly from among those with matched characteristics. Patients were matched on age at surgery, year of surgery, Gleason score, T stage, margin status, postoperative ADT, and pelvic nodal RT. In this way, they were able to generate 366 matched pairs of patients. This technique works quite well in predicting outcomes of prospective randomized trials as long as there is a large enough sample size, considerable overlap in patient characteristics (which there was), and there aren’t any prognostic patient characteristics that were missed.

The researchers found that all measured outcomes were significantly better among those who received ART:

  • 12-year freedom from biochemical failure: 69 percent for ART vs. 43 percent for SRT
  • 12-year freedom from distant metastases: 95 percent for ART vs. 85 percent for SRT
  • 12-year overall survival: 91 percent for ART vs. 79 percent for SRT
  • Patients who suffered biochemical failure were more likely to have had SRT, have been stage T3b, have had higher Gleason score, had not been treated with lymph node radiation, and had not had postoperative ADT.
  • The advantage of ART was only lost if more than 56 percent of them would have been over-treated, but based on nomograms, no more than 46 percent would have been over-treated (using the assumption that two-thirds were Gleason score 3+4 and one-third was Gleason scoreS 4+3).

Pending confirmation by the randomized clinical trials, this study is our best evidence to date that ART is preferable to SRT. However, there are a few very important caveats:

  • They defined SRT as treatment when the PSA is in the range of 0.1 to 0.5 ng/ml. (They actually call this “early” salvage — a term I would prefer to reserve for radiation when the ultrasensitive PSA (uPSA) is below 0.10 ng/ml.) For uniformity reasons in this 10-institution study, any PSA below 0.10 ng/ml on an uPSA test was deemed “undetectable,” and those treated at very low PSAs were considered to have had ART. They had to use those definitions in their analysis because of the heterogeneous data set with PSAs recorded as early as 1987 (before there were any ultrasensitive PSAs). Because the risk of over-treatment with ART is high (they estimate 33 to 52 percent), it behooves patients to track their post-prostatectomy PSA with an ultrasensitive test. We have seen that for men with adverse pathology, any uPSA over 0.03 ng/ml reliably predicts that it will keep going up to 0.2 ng/ml (see this link). In men without adverse pathology, only a convincing pattern of PSA rises is prognostic.
  • Adverse pathology in this study included anyone with positive margins, but others advocate that the length of the positive margin and the Gleason score at the margin are important considerations. A patient with focal positive margins and a Gleasion score of 6 at the margin may never need additional ART or SRT.
  • They lumped together men whose PSA was undetectable but then climbed higher and men whose PSA was persistently elevated after prostatectomy. Persistent PSA with adverse pathology is a clearer indicator that gross amounts of cancer were left behind and calls for some quick action.
  • The Decipher genomic test was not available throughout most of the study period. For those sitting on the fence, it may be a decisive factor.
  • The newer PET scans (Axumin and PSMA-based) can find metastases if PSA is > 0.2 ng/ml. Multiparametric MRI may be able to find sites in the prostate bed or among the pelvic lymph nodes where tumor size is longer than 4 mm. Because of the advantage of earlier treatment, most men will require treatment before metastases become detectable. Some will be over-treated if the cancer is already systemic.
  • Among very high risk patients (i.e., Gleason scores of 8 to 10, seminal vesicle invasion [T3b] or invasion of nearby organs [T4], and very high persistent PSA), the probability that ART or SRT will be curative may be very low. Patients should understand what the population-based risk is from a nomogram.
  • The radiation doses delivered were at a median dose of 66 Gy. More recent evidence suggests that higher doses may be necessary to achieve a cure. The value of adjuvant ADT and whole pelvic radiation suggested here has also been suggested by a number of other studies.
  • This study excluded patients with detected positive lymph nodes. That is a clear indication for ART.

There are many factors to consider including comorbidities, continence, and potency recovery. This will seldom be a straightforward decision. Patients with adverse pathology and a uPSA > 0.03 ng/ml should be talking to a radiation oncologist and not a urologist.

Editorial note: This commentary was written by Allen Edel for The “New” Prostate Cancer InfoLink.

3 Responses

  1. Dr. Edel,

    Thank you very much for this excellent review. I have just one question: Wouldn’t it be necessary to better define the interval between surgery and post-op PSA measurement because of the PSA half-life?

  2. Another great analysis Allen — this question comes up so frequently amongst our participants. … Thanks for your time!

  3. Richard:

    The interval between surgery and the first post-op PSA didn’t really enter into their analysis. It is typically about 3 months, which is plenty of time for any residual serum PSA to be eliminated. They defined “adjuvant” as treatment before any PSAs were taken or PSAs less than 0.1.

    Rick:

    My pleasure. Next to the initial treatment decision, and dealing with the SEs of treatment, the decision about whether and when to have A/SRT comes up most frequently in all my groups. I applaud the researchers who accumulated and processed all the data used in this study. I hope we will someday see a multi-institutional study of ART vs. early salvage (0.03 to 0.09 ng/ml on uPSA) among men with adverse pathology.

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