Who needs aggressive treatment after initial radiation … and who does not?

A new report in Lancet Oncology offers guidance on which patients with prostate cancer who are initially treated with radiotherapy and 6 months of neoadjuvant androgen deprivation therapy (ADT) are at relatively high and relatively low levels of risk for prostate cancer-specific mortality. This paper by D’Amico et al. should be read in conjunction with the associated editorial comment by Saad.

We know that the combination of radiation therapy with 3 years of ADT can extend overall and prostate cancer-specific patient survival compared to radiation therapy alone in men with locally advanced prostate cancer. We know that long-term ADT is associated with significant risk for a range of side effects that can profoundly affect quality of life.  We also know that shorter periods of ADT (e.g., 6 months), when used in combination with radiation therapy, can extend prostate cancer-specific mortality in men with locally advanced disease.

The question that therefore needs to be answered is, how soon and how well can we differentiate between those men who, after an initial 6 months of ADT and radiation therapy, are actually likely to die from their prostate cancer and those who will not.

D’Amico and his colleagues have carefully assessed outcome data from two important trials to try to answer this question.

The Dana-Farber Cancer Institute (DFCI) trial and the Trans-Tasman Radiation Oncology Group (TROG) trial were both designed to compare outcomes of patients given 6 months of neoadjuvant ADT in conjunction with external beam radiation therapy compared to radiotherapy alone as first-line treatments for localized and locally advanced forms of prostate cancer. In each trial, when ADT was administered, it comprised an LHRH agonist and an antiandrogen, and the radiation therapy was initiated at the beginning of the sixth month of hormone therapy. Both trials showed that the addition of 6 months of hormone therapy had at least prostate cancer-specific mortality benefit. (A third arm in the TROG trial was designed to test just 3 months of neoadjuvant ADT + radiation therapy, but these patients are not considered in the current re-analysis.)

To explain the findings from the re-analysis of data from these two trials with care, we need to explain two specific measures of PSA value:

  • The PSA end value is defined as a patient’s PSA level immediately following the completion of radiation therapy.
  • The PSA nadir value is defined as the lowest level that a patient’s PSA reaches at any time after the completion of radiation therapy (and is a value that many patients will be more familar with).

D’Amico et al. have shown that, based on their analysis, a PSA end value and/or a PSA nadir value of > 0.5 ng/ml in men treated with external beam radiation therapy + 6 months of neoadjuvant hormone therapy are surrogate markers for prostate cancer-specific mortality. In other words:

  • If the patient’s PSA end value and his PSA nadir value are both ≤ 0.5 ng/nl, then his cumulative risk for prostate cancer-specific mortality is very low (< 10 percent at 10 years of follow-up), and therefore the only future therapy he is likely to need might be intermittent hormone therapy to manage his PSA and avoid bone pain.
  • If either the patient’s PSA end value or his PSA nadir value are >0.5 ng/ml, then his risk for prostate cancer-specific mortality is significant (20 to 30 percent at 10 years of follow-up) and he should immediately be considered as a candidate for long-term ADT and for trials investigating the use of drugs that have been shown to extend survival in men with castration-resistant prostate cancer (CRPC).

The implications of these findings are considerable because they allow us to know early on — and with accuracy — which patients are at real risk for significant progression post-radiation, and to channel these patients to long-term ADT and to appropriate trials of newer forms of therapy, while simultaneously avoiding the over-use of ADT in men who are probably going to do very well and may only require limited and intemittent ADT in the future.

Now it should be noted that the forms of radiation therapy used in the DFCI and the TROG trials used lower doses of radiation and were potentially less effective and less safe than the forms of radiation therapy used today. However, one could reasonably argue that this only increases the likely accuracy of the surrogate markers identified by D’Amico et al. The authors are also careful to point out that their study assumes that currently available forms of salvage therapy for patients with a rising PSA post-radiation are not very effective (which is true). If salvage therapies for this group of patients were to improve (through the use of salvage HIFU post-radiation, for example), then the current suggestions would need to be re-assessed yet again.

It is also appropriate to note that men with PSA end or PSA nadir values ≤ 0.5 ng/nl after treatment with external beam radiation therapy + 6 months of neoadjuvant ADT do still have some risk for prostate cancer-specific mortality, although this risk is definitely low at 10 years of follow-up.

The “New” Prostate Cancer InfoLink thanks Dr. Anthony D’Amico for kindly providing a prepublication copy of the full text of this important paper for our careful scrutiny.

2 Responses

  1. Couple of comments here …

    Accepting that this study focuses on a different issue, there are studies showing a positive benefit from both 18 and 28 months combined with radiation, as well as the 3-year study mentioned above. According to Mack Roach, no study has been done to date to determine what period of hormone therapy is optimal.

    I have a question with respect to D’Amico’s study that I have not yet read in the original. How do they determine the nadir taking into account a possible spike? The hormone therapy should drive the PSA down to < 0.1; as the hormone therapy wears off, the PSA must rise initially, so it is hard to determine a nadir. It is also hard to predict how the PSA will behave post-hormone therapy. While studies have been done on the return of testosterone after hormone therapy, little work has been done on the behavior of PSA. I was only able to track down one study that much confirms D'Amico's finding: when the PSA stabilizes at < 0.4, outcome is way more positive (I forget the actual measures used).

    Anecdotally, the difficulty that arose in my case, and in at least in one other with a similar treatment protocol of which I am aware, is that the PSA rises significantly when it first comes back before falling. In my case, with 27 months of Lupron alone, it rose to 0.9 ng/ml within 12 months of completing hormone therapy; it has steadily declined in the following 12 months to 0.2 ng/ml, and Roach just wrote me he expects that to continue. In my buddy’s case, he had 12 months of combined androgen blockade (Lupron + Casodex); his PSA also rose to around 0.9 ng/ml within 6 months of completion and has now fallen to 0.65 in the past 3 months.

    While the 0.5 cut-off offers comfort, the problem of establishing a nadir and the pattern of PSA post-hormone therapy complicates matters.

  2. Rick:

    I don’t think anyone is suggesting that an 0.5 cut-off is a perfect tool. It is a means by which to offer guidance.

    I also think that Dr. D’Amico would say that you can really only apply this cut-off to men treated in strict conformance with the structures of the DFCI and TROG trials … when 5 of the 6 months of ADT was being given prior to the start of radiation therapy.

    With regard to the good Dr. Roach’s (accurate) observation that “no study has been done to date to determine what period of hormone therapy is optimal,” I would merely observe that the D’Amico data make it very clear that one has to add the question “optimal for whom?” In other words, what is apparently needed are a series of studies testing several levels of hormonal therapy in carefully stratified groups of patients. No one period of hormonal therapy is going to be optimal for all patients because some men apparently only need a brief period of neoadjuvant ADT whereas others are going to need longer-term ADT (some treated with intermittent and some with continuous therapy). The conduct of such studies would keep the successor to the RTOG going for years … if the NCI has any money to fund the studies!

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