The role(s) of hormone therapy in treatment of patients with biochemical recurrence after first-line treatment for early stage disease

A Brutal Introduction

The possible roles and types of hormone therapy that can be used in the treatment of men who have a rising PSA after “curative” first-line therapy for early stage (localized) disease are many and diverse. So it might be best if we got a few things absolutely straight, right up front!

  • First, and most importantly, in the 60+ years since the first recognition of the value of hormone therapy in prostate cancer, there has never, ever been a definitive, randomized, double-blind clinical trial showing that any form of hormone therapy has any effect on the overall survival or the biochemical progression-free survival of men who were receiving salvage treatment following failure of first-line treatment given with curative intent.

You may find that hard to believe. So do most people. But it’s true!

We should, however, point out that trials that do meet these criteria are now ongoing (see the section on investigational salvage therapies after failure of first-line treatment).

  • Second, and nearly as importantly, the lack of such sound clinical data has led many people (physicians and patients) to develop what we can only describe as “faith-based” beliefs about the use of hormone therapies in salvage situations. And these beliefs are often strongly held, regardless of the lack of actual clinical evidence to support them.

Arguing the merits and flaws of such beliefs is not usually a very constructive pastime (in our experience).

  • Third, and of real, practical importance, hormone therapy may certainly be able to “manage the PSA” of a man who has hormones as a component of his salvage care, but it may not really be managing his risks for progressive disease, because hormone therapy is never curative and does not necessarily extend survival.

The Theoretical Options for Hormone Therapy Alone

Let’s see if we can create a list of all the forms of “simple” hormone therapy that might reasonably be presented to you as options if you had a rising PSA after first-line surgery or radiotherapy tomorrow. They quite certainly include the following:

  • LHRH agonist therapy alone, with a drug like leuprolide acetate (which is commonly used but is certainly not curative)
  • LHRH antagonist therapy alone, with degarelix (which is now theoretically possible but not curative)
  • Antiandrogen therapy alone, with a drug like bicalutamide (which is also common but not curative)
  • 5α-Reductase inhibitor therapy alone, with a drug like dutasteride (which would be unusual and not curative)
  • Combined androgen deprivation or ADT2, with a combination of drugs like leuprolide acetate and bicalutamide (which is common but not curative)
  • Peripheral androgen blockade,” with a combination of an antiandrogen and a 5α-reductase inhibitor (which would be relatively unusual and not curative)
  • So-called “triple ADT” or ADT3, with a combination of drugs like leuprolide acetate, bicalutamide, and dutasteride (which would be unusual and not curative)

So … what do we know so far? 

We know that no form of hormonal therapy, used on its own in a salvage setting, has a hope in heck of curing your prostate cancer! Since many men who are in need of salvage therapy still believe (with some justification) that their cancer can be cured, there seems to be little point to using hormone therapy alone.

Combining Hormone Therapy with Salvage External Beam Radiation Therapy

We do know something very important about the combination of hormone therapy and external beam radiation therapy (EBRT).

We know that when this combination of types of treatment was used to treat men who were initially diagnosed with locally advanced forms of prostate cancer (clinical stages T2b-3N0) in at least two large, randomized, double-blind, multi-center clinical trials, the combination of hormones with EBRT extended biochemical progression-free survival and overall survival compared to either radiotherapy alone or hormone therapy alone!

We still don’t actually know with certainty that the same effect would be observed in the salvage setting, but it would seem like a good potential bet!

Combining Hormone Therapy with Other Forms of Salvage Therapy

When  it comes to knowing whether a combination of hormone therapy with surgery, or with cryotherapy, or with brachytherapy, or with high-intensity focused ultrasound has any effect beyond that of the basic form of salvage therapy offered … we have no real idea at all.

It may sound like a possibility. It may “feel like” a good idea. Some physicians may even tell you that they “get good results” by doing it. The truth is still the same. We have no good, comparative, clinical data to sustantiate any (let alone all) of the “feel good” hypotheses!

So Why Use Hormone Therapy as Part of Any First-line Salvage Technique?

That’s a very good question. And perhaps Moul et al. have answered it the best:

While hormonal therapy results in dramatic tumor shrinkage and offers tremendous relief of symptoms for metastatic disease, its role for nonmetastatic PSA-only recurrence is controversial due to the fact that hormonal therapy is not benign. The negative impact on quality of life can be significant — hot flashes, bone loss, increased fracture risk, sexual dysfunction, loss of libido, memory loss, increased fat deposition, loss of muscle mass, and other metabolic changes (increases in cholesterol, insulin resistance) that may increase the risk of heart disease. … Despite these negative effects, in well-selected patients, the possible benefits of delayed metastasis, reduced skeletal morbidity from metastasis, and prolonged survival may outweigh the risks and justify its use.” [Red italic type added for editorial emphasis only.]

Moul and his colleagues have suggested (or at least implied) certain very specific scenarios in which it is arguable that hormone therapy, either alone or combined with other forms of treatment, may be beneficial. We aren’t going to try to go into all the arguments in detail. This debate has been going on for nearly two decades. Our goal here is only to try to give the reader some practical guidance as the basis for further discussion with his doctor.

  • Early hormone therapy may be a good idea for at least some patients. Two randomized clinical trials (of ADT and ADT2 in the treatment of probable micrometastatic disease) have suggested that early hormonal therapy may extend prostate cancer-specific survival compared to delayed hormonal therapy. And two retrospective analyses of large series of men being treated with hormones in a salvage situation have suggested that early hormonal therapy may extend prostate cancer-specific survival in men at high risk. Thus, for men at high risk for further progression after an initial biochemical recurrence, hormonal therapy in combination with an appropriate form of potentially curative salvage therapy may be beneficial.
  • Retrospective analyses of prospectively collected data from the three trials of the Early Prostate Cancer Program, which has compared high-dose bicalutamide therapy (150 mg/day) to placebo therapy in patients with early and progressive stages of disease, appears to show that certain subsets of patients do well on the active regimen whereas others do poorly.
    • Among men with locally advanced disease (stage T3-4N0-1 and stage T2-4N1) daily high dose bicalutamide has been associated with a 40 percent increase in biochemical progression-free survival and a 20 percent improvement in overall survival.
    • Also, among men with advanced (micrometastic?) disease, daily high-dose bicalutamide (a) decreased risk for biochemical progression by 44 percent and by 25 percent in men who had had prior radiotherapy and prior radical prostatectomy respectively and (b) was associated with a 35 percent improvement in overall survival for men who had had prior radiotherapy.
    • It does have to be recognized, however, that high-dose bicalutamide is associated with breast enlargement and tenderness in up to 70 percent of patients (although these side effects can be managed with either tamoxifen or prophylactic breast irradiation).
  • The last sets of data come from studies of the 5α-reductase inhibitors (finasteride and dutasteride) alone, low dose antiandrogens alone, or 5α-reductase inhibitors in combination with low-dose antiandrogens. It is clear from several such studies that these types of monotherapies or the combined “peripheral androgen deprivation” can be used to establish control over patients’ PSA levels for as much as 5 years, with a limited risk from adverse reactions. However, there are no data that show any form of survival benefit based on such studies.

What is the Bottom Line to the Use of Hormones in Salvage Therapy?

It would appear that there are a few absolutely definitive statements and a few pieces of general guidance that may be helpful, as follows:

  • There are no data from trials in the salvage setting that can demonstrate that hormone therapy alone extends overall or prostate cancer-specific survival in this situation.
  • There are some data that suggest (at least in some carefully selected patients) that hormone therapy, combined with another therapy that is administered with curative intent, may be able to extend survival overall and cancer-specific survival in the salvage setting
    • The most likely such combination of therapies is the use of ADT or ADT2 in combination with EBRT in men with biochemical recurrence after radical prostatectomy
  • Hormone therapies — particularly forms of hormone therapy that involve LHRH agonists, LHRH antagonists, and/or antiandrogens — all come with significant risks of adverse reactions that can profoundly impact quality of life.
  • Some well-structured, double-blind, multi-center clinical trials of hormone therapies with curative salvage therapies vs. curative therapies alone in the salvage setting are desperately needed to clarify the potential value of hormone therapy in these settings. The earliest such trials are getting close to completion.
Content of this page last reviewed and updated December 31, 2008
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