Chemotherapeutic Agents
in the Treatment of Hormone-Refractory Prostate Cancer
Last Revised January 6, 1996
{Developments since this was written may change the information.]
Introduction or "Does Chemotherapy Work?" |
Agents that appear to have some benefit |
Combination chemohormonal therapies |
The importance of patient benefit
Introduction or "Does Chemotherapy Work?"
It is certainly true that until comparatively recently there was almost no
evidence whatsoever to suggest that any form of cytotoxic chemotherapy had
significant value in the treatment of prostate cancer!
For several years, Dr Mario Eisenberger has used a slide which has become
famous as "Eisenberger's spaghetti curves" on which he had superimposed the
clinical results of every significant clinical trial of chemotherapeutic
agents for the treatment of late-stage prostate cancer. The clear picture
presented by this slide was that not one of the forms of treatment
attempted prior to the early 1990s appeared to have any greater value than
any other. Indeed, it was generally agreed that the overall response rate
to chemotherapy appeared to be be about 5-10% with about an additional 15%
of patients having a brief period of disease stabilization.
Here is a brief list of all of the different chemotherapeutic agents which,
when used alone, have been clearly shown to be ineffective or at best
minimally effective in the treatment of hormone-refractory prostate
cancer:
- Cisplatin
- Mitoguazone
- Somatuline
- Trimetrexate
- Vinblastine
- Doxorubicin
- 5-Fluorouracil
- Cyclophosphamide
- Mitomycin
Since many (indeed most) of these cytotoxic pharmaceuticals also have potentially severe
side effects, their value as single agents in the treatment of
hormone-refractory prostate cancer should be seriously and justifiably
questioned, despite the fact that many of these agents have had great value
in the treatment of other forms of cancer. Perhaps the odd thing is that we should have
considered that treatment with single chemotherapeutic agents would even be likely
to offer clinical benefit in prostate cancer: they don't usually work alone in
other forms of cancer!
In recent years, chemotherapeutic regimens for most forms of cancer
have been much more likely to
involve two or more cytotoxic agents which each have some activity on their own
but whose effects are clinically different, so that there is increased likelihood
of clinical responses. However, to date, few purely cytoxic combinations appear to have
had any more success in the treatment of hormone-refractory prostate cancer
than have the single agents.
Agents that appear to have some benefit
There are cytotoxic agents which appear to have some clinical benefit
in hormone-refractory prostate cancer. However, to date none of these agents
(when used alone) appears to be much more valuable than the traditional
chemotherapies. Their value generally appears to be that they operate by different
mechanisms than traditional chemotherapeutics. These products include
- Estramustine phosphate (Emcyt)
- Paclitaxel (Taxol) and perhaps other taxanes such as docetaxel
(Taxotere)
- Navelbine
- Mitoxantrone
Estramustine phosphate and paclitaxel are both what are known as
"antimicrotubular" agents, which means they have direct effects certain
specific structural components of cancer cells. Estramustine phosphate
was, in fact, initially believed to be just another form of estrogen
therapy
However, trials with these drugs when used alone have not produced any
truly outstanding results. The value of these agents appears to become
evident when they are used in combination with each other or with other
chemotherapeutics.
Combination chemohormonal therapies
Recently trials with new combinations of cytotoxic and hormonal agents have
offered superior responses in the treatment of hormone-refractory prostate
cancer. However, in understanding these effects it is important for the
patients to recognize the meaning of a number of terms commonly used in the
discussion of clinical responses to chemotherapeutic agents:
- A complete response or CR is a response in which there is
a very significant reduction in the signs and symptoms of the patient's
cancer (e.g., reduction in the size of all or most metastases) for a significant
period of time (e.g., 3 months or more) in patients with well-defined measurable
disease. (The precise definition of a
complete response can vary from trial to trial and from study group to study
group.)
- A partial response or PR is a response in which there
is a notable reduction in the signs and symptoms of the patient's cancer
(e.g., reduction in the size of about 30-50% of metastases) for a period of
time in patients with well-defined measurable disease.
- An objective response or OR is either a complete response
or a partial response. Thus the objective response rate is usually considered
to be the sum of the complete and the practical response rates.
- Disease stabilization is cessation of disease progression
without any reduction in the initial disease burden.
One of the first chemohormonal combinations used in the treatment of
hormone-refractory prostate cancer was estramustine phosphate + vinblastine.
This combination has been associated with a significant decline (<50%)
in the PSA level about 40% of the patients and partial responses in some
30% of patients, with a duration of response of between 4 and 7 months.
While this response level is considerably better than responses to
single chemotherapeutic agents, it is hardly an exciting response to
therapy.
More recently, estramustine phosphate has been used in combination with
a product known as etopside. To date, information is only available from
one small pilot study, but this combination produced objective responses in
36% of patients, with 52% demonstrating a >50% decrease in their PSA levels.
The overall median survival of the patients receiving this combination was 44
weeks.
Most recently, estramustine phosphate has been used in combination with
paclitaxel. However the results of this trial are not yet available.
Other chemohormonal combinations which have shown interesting levels of
activity are listed below:
- Doxorubicin + ketoconazole (OR = 58%)
- Doxirubicin + stilphostrol (OR = 66%)
- Mitoxantrone + prednisone (OR = 14%).
One might be tempted to consider that these levels of response are still
very much lower than patients would want to hope for, and this is certainly the case.
However, it is equally clear that some progress is being made toward
improvement of chemotherapeutic opportunities for the treatment of
hormone-refractory disease.
The importance of patient benefit
Daniel Von Hoff and his colleagues at the University of Texas have
questioned the entire set of principles behind the use of chemotherapeutic
agents in the treatment of hormone-refractory prostate cancer. They have,
perhaps very reasonably, suggested that we apply entirely the wrong
criteria to the evaluation of chemotherapeutic agents in the management
of this stage of disease. They consider that rather than thinking in terms of
complete and partial responses, physicians and their patients should think
in terms of the maximum quality of life of the patient.
They applied this thinking in a recent clinical trial of navelbine in the
treatment of hormone-refractory prostate cancer.
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