A new article in The Lancet reports long-term data from a randomized, European, Phase III clinical trial of patients who received either immediate (“adjuvant”) or deferred (“salvage”) post-surgical radiation therapy when their cancer was found to extend beyond the prostate at the time of surgery.
Bolla et al. recruited patients of up to 75 years of age from 37 European institutions. All patients were initially treated with surgery and eligible patients were then randomly assigned to “immediate” adjuvant radiation therapy (at a dose of 60 Gy of conventional irradiation to the surgical bed for 6 weeks) or to radiation that was deferred until biochemical progression had occurred (with biochemical progression assessed by at least two PSA levels > 0.2 ng/ml each assayed at least 2 weeks apart). Eligible patients had to have pT2N0M0 or pT3N0M0 disease post-surgery and at least one of the following additional risk factors: extracapsular extension, positive surgical margins, or seminal vesicle invasion.
Details about this trial can be found in the abbreviated trial protocol on the ClinicalTrials.gov web site.
Here is a summary of the key trial results:
- The trial initially enrolled 1,005 patients.
- 503/1,005 patients were randomly assigned to deferred radiation therapy.
- 502/1,005 patients were randomly assigned to adjuvant postoperative radiation therapy.
- The average (median) follow-up is now 10.6 years (range, 2 months to 16.6 years).
- Compared to deferred (“salvage”) radiation therapy,
- Immediate, adjuvant radiation therapy had a significantly beneficial impact on biochemical progression-free survival (60.6 vs. 41.1 percent; hazard ratio [HR] = 0.49; p < 0.0001).
- Immediate, adjuvant radiation therapy had a numerical, but not a statistically significant, beneficial impact on risk for clinically progression-free survival (70.3 vs. 64.8 percent, HR = 0.81, p = 0.0539).
- Immediate, adjuvant radiation therapy had a comparable effect on risk for evident metastatic disease (HR = 0.99).
- Immediate, adjuvant radiation therapy had a comparable effect on risk for prostate cancer-specific mortality (3.9 vs. 5.4 percent).
- Immediate, adjuvant radiation therapy had a comparable effect on risk for overall survival (76.9 vs.80.7 percent).
- Immediate radiation therapy was associated with a more frequent occurrence of late adverse effects of any type or grade (10-year cumulative incidence, 70.8 vs. 59.7 percent; p = 0.001).
In other words, although adjuvant postoperative irradiation did improve biochemical progression-free survival and local control compared with deferred (“salvage”) radiation therapy in this group of men at 5 and 10 years of follow-up, the improvements in clinical progression-free survival were not maintained over time.
The authors note that “exploratory” analysis suggests that adjuvant postoperative irradiation might improve clinical progression-free survival in patients younger than 70 years and in those with positive surgical margins, but could have a detrimental effect in patients aged 70 years or older.
The bottom line to this study is that it leaves us with the same problem that we have had for a while. There are no compelling data that clearly show a meaningful survival benefit for early, adjuvant radiation therapy as compared to salvage radiation therapy in this group of patients. However, this does not mean that it is inappropriate to give immediate adjuvant radiation therapy to appropriately selected patients at clear risk for progression because of a rising PSA post-surgery. It just means that this is going to be a judgment call based on the opinions of the individual physician and the wishes of the individual patient.