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Using adjuvant versus early salvage radiation therapy (RT) after radical prostatectomy in men with pN1 prostate cancer has been associated with reductions in mortality, but is this true regardless of the number of positive lymph nodes? A new study suggested that the number of nodes is an important factor.

Anthony D'Amico, MD, PhD, of Brigham and Women's Hospital and Dana Farber Cancer Institute in Boston, and colleagues explored this question in a cohort of 17,913 men treated from 1995 to 2017, with a median follow-up of 7 years. Importantly, their analysis adjusted for the time-dependent use and duration of androgen-deprivation therapy, they said.

As the team reported in the adjuvant versus early salvage RT was associated with lower all-cause mortality risk, and this benefit increased with each additional positive pelvic lymph node. Specifically, there was an 8% risk reduction for every additional positive node (HR 0.92, 95% CI 0.85-0.99, P=0.03).

However, the absolute risk difference for adjuvant versus early RT was not statistically significant in men with one to three positive nodes (14.27% vs 13.89%, 95% CI -7.02 to 7.70). The difference achieved statistical significance only in men with four or more nodes (7.74% vs 23.36%, 95% CI 5.90-25.35), the study found.

"Given these considerations, these findings provide evidence to support considering the use of adjuvant RT in men with pN1 prostate cancer and using a personalized approach on the basis of the number of positive pelvic LNs [lymph nodes] and other comorbidities," the researchers concluded.

In the following interview, D'Amico, chief of the Division of Genitourinary Radiation Oncology, discussed the implications and further aspects of the study in more detail.

Why do you think the difference was statically significant only in men with four or more positive nodes?

D'Amico: There is a significant difference across the board, but it's relatively small -- 1-3% reduction in mortality ~ 7 years -- for a single node, or two or three nodes. It's much larger -- 10-15% at 7 years -- for four or more nodes, so you can statistically measure a difference.

But if you have an individual patient, and he has one or two positive nodes, and you're trying to decide if he should be treated in the adjuvant or early salvage setting, that comes down to your decision-making with the patient: What's the toxicity of the treatment? What are the patient's wishes? And how is the rest of his health, is he likely going to live a decade in order to benefit from this? That's how I would look at it.

What are the clinical implications of your study's findings?

D'Amico: I think it changes the game a little bit. This particular paper does not have a randomized trial correlate. All the randomized trials of early salvage versus adjuvant did not include men with node-positive cancer to any significant degree, so this is the only data in this space. I think what it does is, for a person who is otherwise healthy who has multiple nodes at prostatectomy, this argues strongly for using adjuvant as opposed for waiting for the PSA to become measurable.

Your study adjusted for the time-dependent use and duration of androgen-deprivation therapy. Did this differ from previous studies, and why was this important?

D'Amico: The reason that is important goes back to 1999 when the study was published in the New England Journal and updated about 10 years later in the Lancet. That study randomized men who had positive nodes and surgery to hormonal therapy immediately or delayed, and there was a large survival benefit. So if you don't adjust for the use of hormonal therapy you can completely confound your results.

This is what makes our study unique compared to prior studies that didn't do this. Hormonal therapy itself reduces mortality in patients with positive lymph nodes after surgery, so you have to adjust for that. You have to adjust not only for whether they did it or not, but the time-dependent part means how long did they do it for, and when did they do it? Did they do it right upfront for 2 years, or did they do it 2 years later for 6 months?

All of that is important, because to get the optimal benefit from hormonal therapy you want to give it upfront and usually for at least 2 years. So we adjusted for when they gave it and how much they gave to make sure we were not masking or coming up with a survival benefit for early versus late radiation which was really being driven by long-term hormonal therapy use earlier rather than later.

Is there anything else you want to make sure oncologists understand about this study?

D'Amico: I think the most important thing, as I said earlier, is there is no ongoing or previously published randomized trial in this patient population asking this question. So the RADICALS, the RAVES, the GETUG studies, all of which were published in the Lancet or Lancet Oncology last year, all had to do with men who underwent radical prostatectomy who got early salvage versus adjuvant radiation.

But those were all men who did not have node-positive disease, so there is nothing addressing this question. I think it's important for people to know this is stand-alone evidence on this topic.

I think the results are sensible in that, knowing you found positive nodes in surgery, there likely are more remaining. Very unlikely you just found the one positive node that was there. So if you found one and you only sampled a few nodes in total, there's probably at least one more there, and leaving it there unaddressed is probably not wise.

Do you plan any additional research in this area?

D'Amico: Yes, this is the second of a three-part study. The first one was published almost a year ago now in the . It looked at men who were not in those randomized trials to any significant degree, men with very high-risk disease, like Gleason 8, 9, or 10, an extension of the cancer beyond the prostate, and we found a very similar thing. In those men there appeared to be a benefit to adjuvant versus early salvage. Then with the current study we looked at the node-positive patients.

And now, PSMA PET has become widely available for use in the postop setting -- and it should, it's a very good study -- but inadvertently what's happening is some healthcare providers are saying well, right now he has a PSA of .1, he's just failed. I can't get a PSMA PET that's going to have an accurate read and more likely to be approved by insurers until it's .2 or .3, so I'll wait until the PSA is .2 or .3 and then I'll get the PSMA PET and we can direct the radiation and/or systemic therapy better.

The problem with that approach is, what happens if waiting until .2 or .3 confers a mortality increase because you've let the cat get out of the bag, so to speak? So the study we're doing right now is looking to see if you offer adjuvant treatment, be it radiation or hormones, or both, at the time when the PSA is .1, as opposed to waiting, do you gain a mortality reduction?

In other words, by waiting, does the risk of death increase?

Read the study here.