Re-thinking the application of hormone therapy


There has long been discussion about the appropriate and inappropriate uses of androgen deprivation therapy (ADT) in the management of progressive prostate cancer. The “New” Prostate Cancer InfoLink has regularly commented on the inherent dangers of using ADT to “manage PSA levels” as opposed to managing a patient’s actual clinical condition.

Last December, Peter Whelan, a prostate cancer specialist practicing in the north of England, published an article on the newly approved 6-monthly formulation of triptorelin emboate. Now, in a “Beyond the Abstract” commentary on the UroToday web site, Whelan has suggested, with some passion, that it is time for the prostate cancer treating community to seriously rethink the timing and use of hormone therapy in order to optimize its value.

Whelan makes the following key points:

  • Hormone therapy for prostate cancer is — at base — a palliative form of care, and when used in men with late stage, metastatic disease, it has a long history of great value.
  • The “standard” use of hormone therapy in recent years, however, has been to control PSA levels, not the patient’s cancer, while taking minimal account of the actual PSA level, its velocity of rise, or the medical and social circumstances of the actual patient.
  • The development of a new clinical condition, hormone refractory non-metastatic prostate cancer, is a direct consequence of this use of hormone therapy.
  • Prostate cancer, when diagnosed early, is a disease with a 20-year time course; using a palliative form of therapy early in the process of progressive disease should be done only with careful consideration, and for the shortest possible period of time, based on individualized assessment of the patient.
  • In general, hormone therapy “should be put back to near the end of the disease course” when it offers predictable benefits of at least 2-3 years good quality of life for many men, “even with the cancer at its most advanced.”

Whelan’s overarching point is that early, long-term use of the traditional forms of hormone therapy, based on the LHRH agonists, is associated with significant risk to a patient’s quality of life. He implies that sacrificing a patient’s quality of life to manage levels of a tumor marker that are of limited clinical significance makes very limited sense.

Whelan also makes the specific point that when early application of hormone therapies really are known to have a survival benefit (e.g., in combination with external beam radiation in the patient who needs radiation therapy for locally advanced, high-risk, progressive disease), they should be used for the shortest possible period of time (e.g., 6 months rather than 3 years). While he does not explicitly say this, we would also assume that he is not generally an advocate for the use of hormone therapy in more advanced forms of disease unless there are strong indicators such as a rapid PSA doubling time or clear clinical signs such as a positive bone scan or early symptoms of bone pain.

The “New” Prostate Cancer InfoLink agrees with Dr. Whelan that if the short-term goal is to turn progressive (as opposed to truly localized) prostate cancer into a chronic disease, an important question is going to be what we can do before we have to resort to the traditional forms of hormone therapy. Can chemotherapy, the new vaccine therapies, and other innovative agents be better used early to arrest the initial development of metastatic disease? Will intermittent use of drugs like abiraterone actetate and MDV3100 before LHRH agonist-based therapy have a greater long-term benefit and fewer adverse effects than the use of current forms of intermittent hormone therapy? It is certainly time for us to begin the concerted attempt to answer such questions — in the best interests of all the men who are at real risk for progressive and potentially metastatic forms of prostate cancer.

9 Responses

  1. I suggest we should discuss ADT when used as adjuvant therapy in a different context to early use of extensive ADT for recurrent disease.

    The past 2 or 3 years have seen the general acceptance of intermittent therapy managed by PSA levels; that is a large step in the direction of making hormone therapy more enduring while also preserving QOL.

    When used as adjuvant therapy, ADT can be curative rather than palliative; even so the same argument may apply and less may be better than more. In a consult this morning, Dr. Ryan (UCSF) made this point to a buddy of mind with extensive locally advanced disease.

    The research has not been done to show whether 12 months is as effective as 18, 28, or 36. According to Ryan, we do know that the first 12 months seems to be the most important period in which to contain the disease.

    As for the closing paragraph, I can only agree that we do not know what impact earlier intervention of recent innovative treatments will have. Three years from now, there may be a new gold standard for adjuvant therapy using one of these treatments.

    rd

  2. There seems to be a bias among some oncologists to “save” treatments for when they are “really needed.” I can understand the bias in psychological terms, after all what doctor enjoys looking a patient in the eye and saying, “There is nothing more we can do for you except relieve your pain”?

    However, if we look at the case of some blood cancers where there has been enormous progress over the years, the key to the progress has been the realization that you have to hit the cancer with combined therapy (three or different treatments at once), which gives the best chance of preventing the cancer from “mutating out of the way” of the treatments as it does when they are given in succession.

    I can’t help but wonder if this bias toward “saving” treatment for later is simply a form of delaying the inevitable rather than aiming for a cure when a cure might still be in reach.

    Admittedly it’s very hard to do clinical trials of an early an aggressive multi-pronged intervention for any but the highest risk cancers. But this could delay by decades the discovery that the right thing to do is hit the cancer early, hit it hard, and hit it from every possible direction. This kind of research needs to be stepped up. We don’t have decades to figure this out.

  3. While not disagreeing with this comment, I think it would be fairer to say that there were “differences of opinion” between physicians who treat prostate cancer about the appropriate initiation of long-term hormone therapy. Large studies conducted to date have shown no benefit from the early use of docetaxel-based chemotherapy with or without hormone therapy in men with high-risk or progressive prostate cancer after first-line treatment. Given the lack of other forms of therapy until very recently, such trials have been few and far between.

    With the potential introduction of new categories of drugs for the treatment of prostate cancer in the near future (e.g., ipilimumab), we may well see new attempts to use these drug early in the disease stage to increase the potential for early treatment with curative effect in men with high-risk and more aggressive forms of this disease. However, it may take a great deal of time to assess the long-term outcomes of such trials.

  4. I have seen posters that suggest early docetaxel does work — unfortunately I do not have the reference, but it is not cut and dried!

    rd

  5. Early docetaxel has shown effects on PSA. What it does not appear to have is long-term effects on time to progression or time to metastasis. It is my understanding that the drug’s manufacturer has abandoned any attempt to demonstrate that early use of docetaxel-based chemotherapy has a clinically significant effect on the progression of prostate cancer in high-risk patients.

    There is still one large, Phase III NCI Intergroup trial (started in 2007) that is recruiting patients. That is the trial of surgery with or without docetaxel and leuprolide acetate or goserelin acetate in treatment of patients with high-risk, localized prostate cancer. The total estimated enrollment for this trial is 750 patients. Frankly, if this trial was one people had any confidence in, it should have been able to recruit 750 patients within a year to 18 months (especially with > 200 study sites).

  6. As always, I both appreciate the article and welcome the opportunity to express a contrasting view from time to time. This is one of those times.

    What Dr. Whelan really seems to be addressing is poorly done hormonal therapy at an early stage, though he is casting a larger net that captures all earlier stage hormonal therapy, which is most unfortunate. For instance, his second point, as quoted in the above article, is that: “The “standard” use of hormone therapy in recent years, however, has been to control PSA levels, not the patient’s cancer, while taking minimal account of the actual PSA level, its velocity of rise, or the medical and social circumstances of the actual patient.” He might have added that so often the doctor is prescribing only the LHRH-agonist (or castration), is failing to monitor to ensure androgen suppression, and is doing nothing to monitor its impact or prevent or minimize the patient’s side effects. Those practices are regrettable indeed! It is even more regrettable that so many in the medical community consider those practices an acceptable standard of care!

    That approach is so foreign to the approach practiced by the pioneering medical oncologists whom I have come to regard as the true experts. In profound contrast to the casual practice above, they carefully monitor not only PSA, using ultrasensitive tests, but routinely monitor testosterone and DHT. Moreover, for years they have not accepted a testosterone of 50 or below as an acceptable indicator of success for the LHRH-agonist or castration; rather they look for the testosterone to be below 20, and if it is not, they find out why and make adjustments, such as shortening the dosing interval or increasing the doses of other drugs. Knowing that that the adrenal glands indirectly produce testosterone in addition to the testes, they counter that with antiandrogen. Knowing that testosterone is still produced despite those measures, they use a third drug, finasteride or Avodart, to sharply reduce the production of DHT from testosterone. They are very concerned about the DHT level and look for it to be <5. (Mine was <3 on this third cycle, during my 10th year of intermittent, maintained triple therapy. If the PSA does not drop to <0.05, which they ascertain with an ultrasensitive test — a practice foreign to so many hormonal blockade dilletantes, and if the other tests indicate successful androgen suppression, they judge that a change in therapy is needed because first line hormonal blockade will not be sufficient! One leading doctor even wants to see the PSA drop to <0.01 or he will consider a change in course. Research in their own practices has suggested that maximum cell kill — not just PSA suppression, requires at least 9 months.

    Moreover, rather than accepting another doctor's conclusion that the patient is hormone refractory, following single, or perhaps even combined hormonal therapy, they will do those crucial testosterone, DHT and other appropriate tests, often finding that suppression of testosterone and DHT WAS INADEQUATE; they have achieved success in overcoming a false hormone refractory state by implementing proper hormonal therapy. It is distressing that so many research studies use a testosterone theshold of 50 as an indicator of a castrate state. At least it is probably somewhat useful as a semi-reliable proxy.

    I have not read the full paper, but I'm disturbed by Dr. Whelan's advocacy of using hormonal blockade "for the shortest possible period of time, based on individualized assessment of the patient." As I noted above, the experts feel strongly that the therapy needs to be at least 9 months in duration, and generally they are looking for durations of 13 to 17 months. They advise potential patients that the side effects are reversible during the vacation periods, but that there is a significant risk of non-reversibility if blockade is continued for 2 years or more and the patient is 70 years of age or older. They are very concerned about "an individual assessment of the patient," as they discovered more than a decade ago that there were risks in hormonal therapy regarding bone density, bone and joint pain, increased ED and decreased libido, mental and emotional state, anemia, hot flashes and sweats, weight gain, muscle loss, and adverse lipid levels. Fortunately, for many years now, they have been advising their patients about countermeasures that have proven to prevent, minimize or eliminate these side effects in their patients. They monitor the whole patient, including cardiovascular aspects, insulin aspects and metabolic syndrome, hypertension, and other threats to health. They urge us to employ countermeasures in advance; my impression is that most of us do very well in minimizing the adverse consequences of blockade if we follow these proven countermeasures. I'm wondering if Dr. Whelan is aware of these risks and aware of the effectiveness of countermeasures. I'm guessing that he is not. If not, there's no wonder why he is opposed to hormonal blockade.

    Perhaps my biggest point of disagreement with his indictment of all hormonal blockade, including well-done blockade, is his and Sitemaster's opinion about the timing. If single blockade were all we had, then perhaps that late timing strategy would make sense. However, I'm convinced, following the experts, that intermittent triple blockade with maintenance, perhaps even just combined blockade, is best initiated early, when the patient is strong and the cancer is weak, as mentioned by another responder. It may be a matter of momentum. It's pretty clear that use of blockade at earlier stages of disease is associated with longer success before the disease becomes refractory. It looks like total blockade is better when the disease burden is lower, when the disease has not built up momentum.

    Those of us who believe strongly in well-done hormonal blockade, initiated early, realize that this is legitimately controversial. The studies just aren't there yet. However, most of us believe in it because we have seen such dramatic and long-term impacts in our own cases and in those of our fellow survivors. We also have come to rely on the demonstrated observation, analytic, and treatment talents of those doctors who have dedicated their practices to prostate cancer patients, a situation that allows for a high volume of observations with thorough follow-up over long periods.

    I'm really looking forward to results of Dr. Sartor's TARP study, the subject of a prior article by Sitemaster. Even though it will be too brief and preliminary to answer some of Dr. Whelan's concerns, I'm expecting that the results will open eyes.

  7. Dear Jim:

    You seem to be overlooking a key issue in this discussion.

    The Johns Hopkins group initially showed that men with progressive disease and a PSA doubling time of > 15 months will likely never have either metastatic disease or significant risk for prostate cancer-specific mortality. The Hopkins data have now been confirmed in other series.

    And yet I regularly see men put onto hormone therapy (regardless of type) with no idea of what their PSA doubling time may be. What is the point of that? It is my belief that it is that type of thoughtless management that Dr. Whelan was referring to.

    The issue of how to best practice hormonal therapy early for those who really do need it (because they have a PSA doubling time of 12 months or less) is a quite different question.

  8. Dear Sitemaster: Wouldn’t any conclusion about PSA doubling time and the need for hormone therapy (or lack thereof) need to take into account the age of the patient and comorbidity? A healthy 50-year-old wilth a PSADT of 15 months and a co-morbid 75-year-old with the same PSADT are not the same.

  9. Dear Dan:

    The available data did, indeed, take account of the age factor. So long as the PSADT stayed at 15+ months, the probability of metastatic disease or prostate cancer-specific mortality was very low.

    Imagine a man of 50 who — on January 1 this year — has a PSA that rises to 0.2 after surgery, i.e., he has biochemical recurrence, and his PSA doubling time is 18 months. This man will be about 64 years of age before his PSA reaches about 100 ng/ml, and most men with a PSA of 100 still don’t have evident metastatic disease. This is assuming that he doesn’t even have second-line radiation at some point.

    Certainly it is the case that being younger with a rising PSA increases one’s risk, but do remember that the vast majority of men still get diagnosed in their 60s rather than their 50s, even today. The argument that several of the specialists at Johns Hopkins have made over the years is that if you can defer hormone therapy in men with a slowly rising PSA for 10 to 15 years, why start early? In such men, hormone therapy commonly works just as well when delivered late. The situation is of course quite different in men with more aggressive disease.

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