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Combined Hormonal Therapy in the Treatment of Advanced Disease

Last Revised November 26, 1995
[There have been further developments in HT since 1995]

Combined hormonal therapy: an introduction | CHT: a general overview | The initial NCI trial: NCI 0036 | The Janknegt trial | Other important trials of CHT for the treatment of advanced prostate cancer | Making sense of meta-analysis | Unanswered questions about the use of CHT | What is intermittent hormone therapy?

Combined hormonal therapy: an introduction

Combined hormonal therapy for the treatment of advanced prostate cancer is not a new idea. It dates back at least to the 1940s, when Charles Huggins and his colleagues first attempted to carry out bilateral adrenalectomies on patients who had already received a bilateral orchiectomy. However, this form of combined hormonal therapy using surgical means was dangerous for the patient and proved to have little long-term value. It was only with the availability of new forms of pharmaceutical in the 1980s that this form of therapy for advanced prostate cancer again became a practical possibility. It remains controversial even today.

Modern combined hormonal therapy (CHT) or maximal androgen deprivation (MAD) is based on the concept that if one could stop all of the male hormones or androgens from being able to have impact on the prostate cells, then one would completely stop the development of new prostate or prostate cancer cells, thereby completely arresting the progression of prostate cancer. Theoretically, this is an appealing concept. However, it should be pointed out immediately that the ability to completely shut down the development of prostate cancer in this way is probably unrealistic; the question is, how close can we get?

Elsewhere, we have already indicated that it was a Canadian physician, Ferdinand Labrie, who initially suggested that by combining treatment with an LHRH agonist (leuprolide acetate) and treatment with a nonsteroidal antiandrogen (flutamide), it might be possible to achieve better clinical effects than by using either drug on its own. While the details of much of Labrie's work have come into question, there is now little doubt that the principle which he suggested has had major impact in the ways in which physicians and patients in many parts of the world think about the treatment of advanced prostate cancer.

CHT is still not absolutely established as the "gold standard" for the treatment of advanced prostate cancer, and in any case CHT can be implemented a variety of differing methods. In these pages we will offer a summary review of all of the major clinical trials which have advanced our understanding of the appropriate use of CHT in the treatment of metastatic prostate cancer. In addition, we will attempt to provide some guidance for patients on the areas which are clearly still controversial.

CHT: a general overview

Well over 20 different randomized trials have now been carried out with the stated purpose of evaluating CHT and comparing it to other forms of hormonal therapy for the treatment of advanced prostate cancer. Despite all this effort, we still do not have any consensus in the urology community. A skeptic could easily come to the conclusion that the "right" trial still had not been carried out!

The first problem that patients need to appreciate is that many of these trials are certainly not good trials. They had more to do with getting drugs approved in different countries around the world than they did with gaining a true appreciation of the clinical value of CHT. The second problem is that at least five more trials used a steroidal antiandrogen (as opposed to a nonsteroidal antiandrogen) in combination with the method of testosterone ablation (e.g., the LHRH agonist). There are serious questions about the value of steroidal antiandrogens in the treatment of prostate cancer, and particularly about their value in CHT.

At the present time The Prostate Cancer InfoLink would suggest that the only forms of CHT which should be seriously considered for the treatment of advanced prostate cancer are the following:

  • (a) An LHRH agonist + a nonsteroidal antiandrogen
  • (b) Orchiectomy + a nonsteroidal antiandrogen.
Certainly these two forms of CHT are those which have been most widely evaluated in the best constructed clinical trials to date, and even then there are outstanding questions.

It would appear that it is possible to draw the following very general conclusions from the large, well constructed clinical trials which seem to meet most of the criteria necessary for a meaningful evaluation:

  • First, CHT appears to extend overall patient survival in patients with stage D2 (or M1) disease by about 7 months, regardless of the ultimate cause of death.

  • Second, there is some evidence to suggest (but not to conclude) that patients with stage D2 (or M1) disease who "only" had low levels of bone metastasis and were otherwise in a relatively good state of health respond far better than patients with later stages of the disease. The only trial followed for long enough to actually establish a difference in survival for such "early stage" patients appears to show a survival benefit of 19 months for patients receiving CHT as compared to patients receiving an LHRH agonist alone.

  • There is little reason to believe that CHT using orchiectomy + a nonsteroidal antiandrogen is either better or worse than CHT administered by using an LHRH agonist + a nonsteroidal antiandrogen.

  • We still do not know whether the survival benefit which appears to result from long-term CHT would in fact be evident if the patients received only short-term CHT to overcome the so-called "flare" reaction which results from initial LHRH therapy. However, since there is no "flare" response to orchiectomy, and at least one trial has now clearly shown that CHT with an orchiectomy + a nonsteroidal antiandrogen had a 7-month cancer-specific survival benefit, it now seems less likely that short-term antiandrogen therapy to prevent flare is as valid as long-term CHT.

The outstanding questions about CHT will be addressed below or in the pages on intermittent CHT, which is an experimental form of CHT currently under clinical evaluation.

The initial NCI trial: NCI 0036

The first major clinical trial ever initiated to evaluate CHT was organized by the National Cancer Institute and became known as NCI 0036 or the "Intergroup" trial. It was initiated in 1984, and there is little doubt that many participated in this trial with the clear belief that it would prove that CHT did not offer any benefit to patients as compared with older forms of hormonal therapy.

According to a story told by one of the principle investigators, they were so keen to proved that CHT didn't work that they tried to publish the results at least twice before the trial reached a point when half of the patients had died (and therefore before the true value of CHT would have been known.)

Over 600 patients were enrolled into this trial, all of whom had stage D2 prostate cancer. Half received an LHRH agonist (leuprolide acetate) + the nonsteroidal antiandrogen flutamide. The other half received the same LHRH agonist and a placebo (a sugar pill that looked like the nonsteroidal antiandrogen flutamide, but actually wasn't.) This type of trial, in which neither the patients nor the investigators know which patient is receiving which form of therapy is known as a double-blind trial. This is important, because many trials are not double blind, which means that the investigators or the patients can affect the results of the trial because of their knowledge.

When half of the patient had died, and the results were analyzed in 1989, it was clear that the patients in the CHT arm of the trial -- on average -- were living longer than the patients in the LHRH only arm of the trial, by about 7 months overall. The US Food and Drug Administration promptly approved flutamide (Eulexin/Schering) as the first nonsteroidal antiandrogen for the treatment of stage D2 prostate cancer patients in combination with an LHRH agonist.

As time progressed, and the data were more carefully analyzed, it became evident that there was a small subgroup of patients in this trial that were going to have a survival benefit that was far better than just 7 months.

Because of the way in which this trial was set up there were equal numbers of patients in each arm of this trial who had so-called "good performance status." As compared to the average patient in this trial, these "good performance status" patients had lower levels of disease burden, with lesser levels of bone metastasis and a generally better quality of life at the time that the trial began. There were 41 such patients in each arm or the trial. By 1992, eight years after the trial had begun, half of each of these two groups of patients had died, and there was a clear survival benefit of 19 months for the patients who had received CHT.

Some physicians have never considered that this trial (or indeed any other) has effectively demonstrated the value of maximal androgen deprivation. It is certainly fair to say that there were many physicians who believed that until the results of this trial were substantiated, it was difficult to justify changing their treatment for advanced prostate cancer on the basis of this one trial. However, as more evidence has come to the fore, the majority of the prostate cancer treatment community now seems to consider that CHT is the preferred form of therapy for patients with clear signs and symptoms of advanced prostate cancer.

The Janknegt trial

For over 40 years prior to 1990, orchiectomy had been considered the "gold standard" for the treatment of advanced prostate cancer. Despite the availability of LHRH agonists and all of the other innovations, it still remains the "gold standard" for the world's urologists because as yet we have not proven that combined hormonal therapy is truly a better choice under all circumstances.

Only two large trials have so far been carried out with the intention of clearly evaluating the benefit of CHT using orchiectomy + a nonsteroidal antiandrogen as compared to orchiectomy + a placebo. The first of these two trials was an international trial carried out by Dr Janknegt and his colleagues. This trial will be discussed here in detail. The second such trial is known as the Southwest Oncology Group trial 8894 (SWOG 8894) or the NCI Intergroup trial 0105; this trial is expected to report its results some time in 1996.

The Janknegt trial enrolled just over 450 patients with stage M1 (stage D2) prostate cancer, and was generally similar to the initial NCI trial discussed earlier. The major differences were as follows:

  • First, patients were randomized to receive either an orchiectomy and a nonsteroidal antiandrogen (nilutamide) or an orchiectomy and a placebo. In other words, this trial replaced the LHRH agonist used in the NCI trial with orchiectomy and used a different nonsteroidal antiandrogen. Otherwise there were few meaningful differences between these two trials.

  • Second, the PSA test was now available to carefully monitor patient progression. At the time of the original NCI trial the PSA test was still in development and so was not available for carefully monitoring patients.

Because the Janknegt trial enrolled a smaller number of patients than the original NCI trial, the results of the trial are not quite as definitive. However, the key results from this trial are as follows:

  • (a) Patients receiving CHT showed signs of disease progression an average of 6 months later than those who received orchiectomy alone.
  • (b) Patients receiving CHT and who died from prostate cancer survived for an average of 37 months, whereas patients who received only an orchiectomy and who died from prostate cancer survived for an average of 30 months.
  • (c) Patients who received CHT were more likely to achieve normal PSA values (and to achieve them faster) than patients who received only an orchiectomy.

The investigators concluded that the combination of orchiectomy and nilutamide was superior to orchiectomy alone in the first line treatment of patients with metastatic prostate cancer. Others were not completely convinced.

Other important trials of CHT for the treatment of advanced prostate cancer

As we have mentioned, there have been many other clinical trials which have attempted to add to our knowledge regarding the potential benefit of CHT in advanced prostate cancer as compared to various forms of hormonal monotherapy:

The problems with these trials is that some included a variety of different patient categories in an unstratified manner, others simply did not include enough patients to allow for differences in the results between the patient groups to become evident, and still others were not double-blinded, which means that patient or investigator knowledge may have prejudiced the trial results. This is critical in evaluating the large trials which have been used to suggest that there is no benefit to CHT.

The European Organization for Research and Treatment of Cancer (EORTC) compared bilateral orchiectomy alone to CHT with an LHRH agonist and a nonsteroidal antiandrogen in patients with stage M1 disease. This trial included 320 patients on whom there was sufficient data to assess survival. After a median follow-up of 5 years, the authors reported a 7 month survival advantage in favor of the group receiving CHT. This result is very similar to the overall result of the original NCI trial, despite the fact that both the patients and their physicians clearly knew exactly which form of therapy that each patient had received.

The Danish Prostatic Cancer Group conducted a very similar trial to the EORTC. Patients were also randomized to receive bilateral orchiectomy or an LHRH agonist and a nonsteroidal antiandrogen. However, no all of the 262 patients entered into this trial had stage M1 disease. A small number had only locally advanced disease. In this trial there was no overall or cancer-specific survival benefit for CHT compared to orchiectomy.

Finally, two other relatively large trials claim to show no benefit for CHT over an LHRH agonist alone. However, both of these two trials included patients with locally advanced and advanced disease; neither trial was double blind; and there are other technical reasons to consider that these trials might be flawed.

Making sense of meta-analysis

There has been a recent trend in medical science to use data from many different trials to carry out what is known as "meta-analysis." Basically, this is a statistical method of putting all the data from several trials together in order to try and make final decisions about the value of a specific type of therapy. Such meta-analysis has been used in attempts to demonstrate the value of adjuvant hormonal therapy in breast cancer, of CHT in advanced prostate cancer, and of other treatments in other diseases.

In mid-1995 a paper in a major English medical journal, The Lancet purported to demonstrate that CHT was not, in fact, clinically superior to hormonal therapy with bilateral orchiectomy or other forms of single hormone therapy. It is the opinion of The Prostate Cancer InfoLink, and of several reputable authorities, that this meta-analysis of the available CHT data was flawed by the inclusion of improperly constructed trials and trials which had used steroidal (as opposed to nonsteroidal) antiandrogens. The Prostate Cancer InfoLink recognizes that there are several unanswered questions about the value of CHT in the treatment of advanced prostate cancer. However, attempting to mix data from very different types of clinical trial does not help to clarify the situation.

Unanswered questions about the use of CHT

[Reminder: This was written in 1995.]

There are a significant number of unanswered questions about the use of CHT in the treatment of advanced prostate cancer (quite apart from its other potential uses which are dealt with elsewhere in The Prostate Cancer InfoLink).

The first and most important question is, "When should a patient start to receive CHT (or indeed any other form of hormone therapy)?" Bluntly, we still don't know the answer to this question. There are a series of potential scenarios:

  • A patient could start to receive CHT as soon as he is diagnosed as having metastatic prostate cancer. The problem with this is that it is very difficult to tell exactly when a patient starts to have metastases. There is no problem when a patient clearly has signs of metastases on a bone scan, and some physicians have suggested that the majority of patients with a PSA of 20 ng/ml or more very likely will have metastases, but as yet there is no definite way to tell that a patient has a microscopic metastatic site of prostate cancer outside the prostate until it becomes apparent on a bone scan.

  • A patient could start to receive CHT once he has clearly failed definitive treatments such as surgery or radiation and his PSA starts to rise. However, we do not know whether this is a good idea. It may be better to delay therapy until the first clear symptoms of metastatic prostate cancer (e.g., bone pain) start to appear.

  • A patient could delay starting CHT until the first clear symptoms of metastatic prostate cancer start to appear. However, is it possible that in this case we will fail to gain the greatest possible benefit from CHT in terms of patient survival?

These are difficult issues. So far there is only one large clinical trial in place which is attempting to answer these questions as they affect the use of CHT in advanced prostate cancer. That trial (SWOG 8894, also known as NCI Intergroup trial 0105) is expected to report its findings at some point in 1996. It is an important trial, constructed by many of the same individuals who constructed the original NCI trial of CHT. Its results are eagerly awaited.

What are some of the other questions to which we would like answers? Well, they include the following:

  • What is the "best" form of CHT? Is one LHRH agonist better than another? Is one nonsteroidal antiandrogen better than another?

  • Might it be possible to carry out "intermittent" CHT with a similar degree of effectiveness as continuous CHT?

  • Can we develop other forms of hormonal therapy which will be better than the presently available forms of CHT?

What is intermittent hormone therapy?

Intermittent hormone therapy is an investigational form of CHT which may offer new benefits to patients and is currently undergoing careful evaluation in clinical trials. It will be some years before we are able to know its true value as compared to other forms of hormonal therapy.

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The content in this section of the Phoenix 5 site was originally developed by CoMed Communications (a Vox Medica company) as part of The Prostate Cancer InfoLink. It is reproduced here with the permission of Vox Medica.

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