Exceptions to "early salvage" radiation treatment for recurrence after prostatectomy

Three major randomized clinical trials and a meta-analysis have proved that for most men waiting for early signs of recurrence after prostatectomy (e.g., 3 consecutive PSA rises or PSA of 0.1 or 0.2 ng/ml) to give radiation gave the same outcome as immediate ("adjuvant") radiation (see this link). But there are exceptions. In some men, adjuvant treatment is better. In some men, early salvage may overtreat them.

Adjuvant Radiation Therapy

Tilki et al. did a retrospective study of 26,118 men given prostatectomies at several hospitals in Germany, UCSF, and Johns Hopkins. 2, 424 of them had "adverse pathology" defined as:

• positive lymph nodes, or
• Gleason score = 8-10, and
• Stage T3 or T4

Patients were treated with adjuvant (within 6 months of prostatectomy) radiation therapy (ART), salvage radiation therapy (SRT) after PSA rose above 0.2 ng/ml (biochemically recurrent - BCR), or no radiation therapy. They matched patients on age, initial PSA, and positive/negative margin status. 10-year all-cause mortality was:

• for men with adverse pathology including positive lymph nodes:
• 14% for ART
• 27% for no RT
• 28% for SRT
• for men without positive lymph nodes:
• 5% for ART
• 25% for no RT
• 22% for SRT
• for men with no adverse pathology:
• 8% for ART
• 9% for no RT
• 8% for SRT

This suggests that for men with adverse pathology, ART improves outcomes over early SRT.

Delela et al. found that a high Decipher score can tip the balance toward adjuvant radiation.

No/Delayed SRT

At the other end of the risk spectrum are men with such low risk for clinical recurrence, that salvage radiation can be delayed, perhaps indefinitely. This is based on the observation that while 40% of post-prostatectomy patients may experience a BCR, only 30% of BCR patients develop a clinically relevant recurrence, and all but 16% die of something else before the recurrent cancer kills them. We saw the results of a retrospective study that suggested that those at lower risk of progression (low PSA, Gleason score, and stage) and receiving a higher dose of SRT may not need adjuvant ADT. 

In a major review for the European Urological Association, Van den Broeck et al. reviewed 77 studies covering 20,406 patients who were biochemically recurrent (conventionally measurable PSA) after prostatectomy. They sought to define the patient and disease characteristics that determined which of the BCR cancers led to distant metastases and death from prostate cancer. They found that the following risk characteristics defined a "low risk" BCR prostate cancer that could be safely watched:

• PSA doubling time > 1 year
• Gleason score < 8
• Interval to biochemical failure > 18 months

Tilki et al. validated the EAU study in a retrospective study of 1,125 patients. Preisser et al. validated the study retrospectively among 2,473 men. Pompe et al. validated the risk group in a retrospective study of 1,821 men. To date, there has been no prospective validation in a randomized clinical trial.

(update 5/4/23) Tilki et al. found that if there was one high-risk feature (stage T3/4 or GS 8-10) and PSA ≤ 0.25, salvage radiation provided no survival benefit. However, the survival benefit was significant if PSA>0.25. This suggests that post-prostatectomy patients with a high-risk feature must not wait for the results of a PSMA PET/CT (which usually is uninformative below PSA of 0.5), but should have salvage radiation as soon as they are biochemically recurrent.

Zaorsky et al. point out some additional characteristics of recurrent patients who may be safely watched:

• PSA < 0.5 ng/ml at time of recurrence
• Age > 80 years of age
• Significant comorbidities
• No distant metastases detected with PET/CT imaging (Ferdinandus et al)

It is undoubtedly better to have a low Decipher score as well.

Lacking prospective validation, this is a decision that should be carefully discussed between the patient and the radiation oncologist.