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Hormone Refractory Prostate Cancer
Understanding
Treating Maintaining Quality of Life
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CHEMOTHERAPY
FOR HORMONE REFRACTORY PROSTATE CANCER (HRPC) Part
1 A
Patient’s Personal Perspective
SUMMARY As is the case of many
other prostate cancer patients, in the past three years I have exhausted six
hormonal ablation therapies and in May/June 2000 bone pain, PSA, bone scans,
and MRI all reflected disease progression.
Rather than rely on patient testimonials or the advice of one medical
oncologist, I began a search of the peer reviewed trial abstracts to educate
myself regarding what chemotherapy protocol options are available and which
seemed to have a profile that correlated with my objectives. I was naively looking for the agent or
combination of chemo that assured the best cure rate with optimal effect on
Quality of Life (QOL). After a prostate cancer
patient has exhausted all hormonal therapy and pain, PSA, unfavorable bone
scan/MRI (or all of these), reflect disease progression, chemotherapy is
normally the next logical therapy for attempted containment of the
disease. But a major issue is: which
chemotherapy or combinations thereof? As I searched for a chemo
intervention that would contain my disease progression, I became frustrated
that my definition of success is diametrically opposed to that of the reported
trials. To my dismay, after reviewing
several hundred trial abstracts and reading several current books regarding
treating HRPC, a pattern is constant:
1.) the preamble of most trials
say drug X has proven efficacy/activity in vitro for inducing apoptosis in
HRPC; 2.) several profiled men were recruited for the trial and details of
agents, dosing, and scheduling are cryptically listed; 3.)
results are reported as: Response Rates (RR), defined as the percentage
of patients whose PSA decreased at least 50%;
Median Duration of Response (MDR), defined as how many months before
those patients’ disease progressed notwithstanding the therapy; Median Duration
of Survival (MDS), defined as how many months until death; and, 4.) conclusions that invariably say
something like ‘The therapy was well tolerated, active in HRPC, the responses
in this population are very encouraging, and suggest substantial durable
activity for this agent, etc.’. Yet, the investigators have
just reported a trial that had numerous toxicities of neutropenia, anemia,
neuropenia, atrial fibrillation, endema, hyperglycemia, anorexia, myalgias,
alopecia, possibly some deaths, etc. along with a RR of 40-60%, MDR of nine
months, and MDS of 12 months, at best.
Therefore, my naive definition of my objective of tolerating several
months of unpleasant side-effects for several more years of disease containment
were shattered. And, after reading Klein,
Management of Prostate Cancer I realize that my disease is not
curable (I subconsciously knew that) and chemotherapy, under the new (1997)
National Comprehensive Cancer Network (NCCN) guidelines, has undergone a
paradigm shift in the treatment of prostate cancer that recognizes that
chemotherapy, as it is practiced with existing agents, is palliative only
and provides no survival benefits. (see Klein,
page 289-303) Are patients informed by
their urologist/medical oncologist of this 1997 paradigm shift in the treatment
of HRPC? I have never had a
conversation with a doctor revealing that chemotherapy is palliative only and
even if the patient responds, such response will be for only a few months
before disease progression. Some of my
fellow prostate cancer patient friends knew that chemo was only palliative; but
prior to starting a chemo protocol I did not realize that chemo is palliative
only and even if you respond it has a
progression-free duration of only a few months. Knowledge of this paradigm shift greatly affects the thought
process regarding what to do after exhausting all hormonal therapies and facing
disease progression. With this
knowledge, a HRPC patient might possibly want to explore a program of pain and
symptom control with a doctor skilled in the art of pain management. Thus, the patient could continue surviving
relatively pain free, enjoying the same life survival expectancy, and without
all the unpleasant side-effects of chemo.
His hope and dream of living until the magic bullet arrives might be
enhanced by a treatment program that removes a daily life of constant fear,
dread, and tension (necessarily shared his family and friends) of chemo
treatments and immediate lifestyle altering side-effects. Following a dire diagnosis
and prognosis in August ‘97 of a base PSA of 323.0 ng/ml, D2 (multiple lower
back/pelvis tumors), and Gleason 9, I naively progressed through a local
urologist and subsequently decided (after nine months) that he was beyond his
skill profile and I sought a leading medical oncologist at one of the world’s
leading cancer institutions. Actually,
not much changed. I was still left on
my own to research my own options. The
institutional pattern was carved in stone---do more hormonal manipulations
until progression and then into the chemo suite for a standard offering of a
chemo mixture. I hope my search results
below will assist someone in his decision-making process as he and his family
approach hormonal manipulation exhaustion.
I fully realize that hope springs eternal and I know that ‘medians’ are
a curve with some men failing on the left side of the median and some men
surviving longer than the median on the right side of the curve. I have embarked on a chemo protocol with
just that hope---that I am to the far right of the curve. My life has been a story book of good
fortune and I have every right to believe that someone is guiding and
protecting me (and HE/SHE does not wear a long white coat) and that my program
will provide survival until antiangiogensis, monoclonal antibodies, gene
manipulation, vaccines, etc. will cure my disease or force it into long-term
control. A
Paradigm Shift in the Treatment Management of Prostate Cancer A paradigm is the
philosophy and theoretical framework in which a scientific field formulates
theories and approaches to questions.
Traditionally, patients and doctors (practicing and research) have
focused on lengthening survival or attempting a cure for prostate cancer. However, after many years of attempts to
accomplish these ends, once prostate cancer exhibits clinical hormone
insensitivity, the results of myriad trials and protocols are universally
disappointing and conclude that these therapeutic interventions, especially
chemotherapy, are of little benefit in prolonging survival. During the past few years,
the paradigm has shifted from hoping for a cure or lengthened survival to
recognizing that the immediate goal and objective of therapeutic intervention
with chemotherapy is to palliate pain and symptoms. In 1997 the National Comprehensive Cancer Network (NCCN)
established new guidelines for the treatment of HRPC and such guidelines have
evolved into a broader objective in the standard of care for HRPC patients. The new guidelines stress palliative care
and list three categories: supportive
care with steroids, palliative chemotherapy, and palliative local/systemic
radiation. (Milikan, Oncology 1997;
11:180-193) This paradigm shift in the
management of HRPC emphasizes recognition of palliative end points
(measurements) wherein a current treatment is recognized as failing, the
disease is progressing, and pain is escalating. Current medical thinking is to define these clinical end points
and institute a different therapeutic intervention to regain control of
symptoms. Toward this end, medical
science is again experimenting with alternating chemotherapy combinations,
creating new concepts of combinations, oral chemotherapy (in various
combinations), and development of combined chemo-hormonal therapies. But all these efforts are directed at
palliation and not at lengthening survival, as the hundreds of chemotherapy
trials and protocols of the past few years have been disappointing vis-à-vis
prolonging life. This concentration on
palliative management of HRPC and the end of reliance on survival as the
clinical/trial objectives reflects a major paradigm shift in the management of
HRPC and profoundly affects clinical trials and treatment protocols, as well as
requiring intense reorientation and involvement of patients in the management
of their own quality of life and destiny. Another
Paradigm Shift in Cancer Treatment In 1995 (before the 1997
NCCN paradigm shift in prostate cancer treatment) another paradigm shift was
opened for discussion in a Schipper et al. editorial (J Clin Oncol,
April 1995, Vol 13, No 4). The
rhetorical issue addressed is the fact that for 100 years we have used a model
in which cancer cells are considered different from the host and that those
differences can be exploited therapeutically.
The theory is that unless they are killed and eliminated these cells
will overwhelm and kill the host. All
research, treatments, strategies, and success standards for the past 100 years
are based on this killing paradigm.
This new (?) challenge was to question whether our obsessive killing
strategy is actually counterproductive because it impairs and weakens the host
and destroys an already defective regulatory system of checks and balances in
the host’s immune system. The Schipper suggestion
was that we can no longer approach cancer as we do microbial and virus
diseases, in which we identify an unwanted intruder in the host and kill
it. Rather we must review our 100 years
of disturbing lack of success and inconsistencies with our killing paradigm and
re-consider whether we must kill all cancer cells and cure the host, or must we
recognize a more subtle paradigm based on cellular and intercellular
communication and biologic control?
Thus, we need therapies that address controlling the disease to the
point that the host is not destroyed by the treatment and can live a quality
life with the disease. Toward these ends, this
subtle paradigm cancer treatment shift has opened a new line of thinking,
research, and approaches to cancer therapy.
But, this is paradigm shift theory and prostate cancer patients have
seen very little of this 1995 thought process as we are still left with
therapies designed to kill them all---and none of the therapies have killed
them all or prolonged life. Still
Another (3rd?) Paradigm Shift in Cancer Therapy In a past life B.C. (before
cancer) I had a business partner in the south-eastern Mexican state of Chiapas
and I often visited the area. In the
delightful old colonial town of San Cristobal the houses have been
painted all colors and shades of a rainbow for many decades , with each owner
and decade applying an over-paint of a different hue or color. As these houses are modernized and
rehabilitated and the old layers of paint are removed, layer upon layer of
earlier paint reveals myriad color combinations and a chaotic frescos of bursts
of color contrasts and conflicts. As
this patient tries to understand the nature of the beast that is consuming me,
I am reminded of the conflicting explosion of colors on the Chiapas colonial
houses and shocked at the fresco of conflicts in 100 years of shifting
paradigms of cancer detection and treatment.
There are layers and layers of cancer treatment theories and practices
plastered one on top of the other, each hiding those underneath, but waiting to
be partially uncovered and added to the chaos. The latest cancer treatment
paradigm shift is discussed by Kamen et al. in J Clin Oncol, Vol 18, Issue
16 (Aug), 2000:2935-37 wherein the discussion relates the last two decades
of therapy as focused on an ever-escalating dosing approach based on the
principle that if a little is good, more is better. This high-dose chemotherapy was possible because the technology
of supportive care of the damage done to other cells advanced. But while this theory roared ahead, the
anticipated results of killing them all were less than spectacular. Thus, another ‘new’
paradigm shift is to concentrate on frequent low-dose therapy which targets the
vascular system of the tumor rather than a frontal blitzkrieg intent on
killing every cell in the tumor. This
high-dose mentality (the more you give, the more you kill) resulted from in
vitro models studying the biology of chemo cancer cell kills. But the study from which this theory
developed cautioned that the theory was narrowly limited to specific cells and
did not account for varying cell divisions or differing cell and cancer
characteristics and would be of limited usefulness in vivo. (Schipper et al., Cancer Chemother Rep
54:431-450, 1970 and J Clin Oncol 13:801-7,1995) Yet, notwithstanding these clear caveats, the oncology
practice signed on to the high-dose theory in a wholesale manner and thus, we
were subjected to 30 years of bizarre trials and ineffective protocols. Recent theories propose
that frequent low-dose chemo therapy produces an antiangiogenic effect and
starves the cancer into apoptosis.
Moreover, current theories propose that with constant repetitive chemo
dosing, the timing of exposing the cells to the agent is more important than
the magnitude of the agent dose. For
instance, Hainsworth et al. (Ann Oncol 6:325-341, 1995) demonstrated
that when VP-16 was dosed daily Q21 it had less toxicity and greater efficacy
than a similar total dose in a 24-hour infusion. Kamen introduces a new
catchy paradigm: ‘High-Time’ or ‘High-Time for Low Dose’ chemotherapy that will
shift the emphasis to seeking the longest drug exposure at a given drug
concentration. The theory makes sense;
with a large tumor and a long or unknown dividing/doubling time, saturating it
with a high-dose of chemo for a short time doesn’t make much sense since the
exposure will be brief before the agent passes from the host’s system, and the
toxicities might be unmanageable.
Rather, subject the cancer cells to continuous chemo exposure over a
long time (and thus, be present for any random cell division), while greatly
reducing the toxicity. Therefore, another paradigm
shift in cancer treatment---maximum tolerated doses (MTD) are out, and
repetitive low-dose-limiting toxicities (DLT) are in. Or are they? The latest
trials still pursue MTD while attempting to manage significant toxicities at
the highest doses of chemo. The
Other Side of the Paradigm Shift Coin With the belated official
recognition that chemotherapy agents and combinations thereof are palliative
only and do not cure prostate cancer or prolong life, medical science has begun
emphasis and investigations of novel molecular mechanisms as therapy such as
antiangiogensis, delivery of therapeutic agents via monoclonal antibodies, and
gene therapy that reverse genetic aberrations, restoration of tumor suppression
genes, or stimulating immune systems.
This additional complementary paradigm shift is directed at targeting
therapies to kill/cure prostate cancer and while these theories are still in
their infancy, they hold great promise for the future management of prostate
cancer. Those of us who are dealing
with HRPC (or will do so in the future) have no choice but to manage our
disease with all available palliative therapies while remaining aware of and
being hopeful for the development of new theories and therapies which will kill
our cancer or control progression of the disease and thus, prolong a quality
life. A
Review of Current Chemotherapy Theories and Protocols Paradigm shifts are
intriguing and thought-provoking. But
if your ox is in the ditch (as mine is), I don’t have time for philosophical
discussions about paradigm shifts---I urgently need a therapy that will provide
more quality time as I wait for the magic bullet that will prolong my life. As we face HRPC, certain
thoughts must be recognized as possibly irrefutable: “Hormone refactory prostate cancer is presently incurable.” (Williams,
ASCO Abstract 1463/00) “The
traditional paradigm in prostate cancer has been that once a prostate cancer
exhibits clinical hormone insensitivity, therapeutic interventions, especially
chemotherapy, are of little benefit.” (Klein, Management of Prostate Cancer,
pp. 289) “Hormone refactory
prostate cancer (HRPC) has a poor prognosis, chemotherapy improves symptoms but
does not improve survival.” (Freidland, ASCO Abstract 1237/99) “...no single agent or combination treatment
has demonstrated a survival benefit in patients with advanced,
hormone-refactory prostate cancer in Phase lll trials.” (Oncology, Vol 13,
No 12 December 1999) “Chemotherapy
has been associated with disappointing results in HRPCA...’ (Fairooz, ASCO Abstract 1392/00) What chemo treatment
options are available? With the above thoughts in
mind, as well as the several new paradigms of medical science concentrating on
management of QOL issues and symptom control while waiting for new modalities
for increasing survival, we, as patients, are left with no cure or choice
except alternating chemotherapy agents and combinations/doses to control
symptoms and try to survive with an acceptable QOL until one (or more) of the
latest theories are in meaningful trials. Current palliative
chemotherapeutic agents available as single agents or in anticipated
pharmacokinetic combinations are:
There were hundreds of
clinical trials of these agents (or combinations thereof) from 1997 to 2000,
with re-newed interest in some older agents and one relatively new agent
(Taxotere). It seems that all of these
agents are periodically cycled through attempts at rejuvenating them for all
categories of cancer, always with the hope of discovering a ‘cure’. Alas, to-date, none of the agents or
combinations are believed to have successfully cured or extended life with
HRPC; and meanwhile, some of the created trial attempts at pharmacokinetic
chemo agent combinations border on the bizarre in the search for the right
combination and dosing schedule that might prolong survival. As with all drugs, these
chemotherapeutic agents have cautions and warn of possible toxic effects: reduction in bone marrow function, nausea
and vomiting, mouth sores and ulcers, diarrhea, hair loss, skin changes (rash),
allergic reactions (temperature, shivering, flushing, dizziness, headache,
shortness of breath, anxiety), numbness or tingling in hands or feet, fluid
retention, tiredness, aching joints/muscles.
In drug combinations, these possible effects are increased exponentially
and are difficult to clinically manage. With the prior and new
paradigms for PCa treatment in mind, note that most (if not all) abstract
preambles include some version of “...(some chemo agent) has been shown to have
significant activity in patients with HRPC.” And, “...combinations of (some chemo agents) are synergistic in
vitro and show significant clinical activity in HRPC.” (Emphasis mine.) Caveat Emptor---beware
of treatment planning based on ‘significant activity’ and study the reported
trial results. In most prostate cancer
chemo trials the maximum response rates (RR) are 70%, but most are much lower;
the maximum median duration of responses (MDR) are 9 months, but many are
shorter; and the maximum median duration of survival (MDS) is 12 months, but
most are much shorter. The ‘significant
activity’ at present is at best ‘median’ palliation of pain for less
than one year, and no evidence of prolonged survival---and at what price given
the toxicity of chemo agents and their effect on QOL? SUMMARY REVIEW of prostate cancer trials utilizing chemotherapy
agent(s). TAXOTERE (Docetaxel) Taxotere is a relatively
new chemo agent. It inhibits cancer cell
division by essentially ‘freezing’ the cell’s internal skeleton, which is made
up of microtubules, which assemble and disassemble during the cell cycle. Taxotere promotes assembly and blocks
disassembly of microtubules, thereby preventing cells from dividing and leads
to cell death; it does not discriminate, its activity is effective in all
rapidly dividing cells--the good guys and the bad guys. In 1999/2000 a review of 14
trial results attached as Table 1. reveal: 1.)
single agent infusion of 36-75
mg/m2 resulted in 34-65% patients responding (RR-defined as at least a 50%
decrease of PSA), with a Median Duration of Response (MDR) of 5-9 months and
maximum Median Duration of Survival (MDS) of 12 months. 2.)
when combined with Emcyt, RR was from 31-78% with MDR from 1 to 13
months and MDS a maximum of 18 months. While Taxotere (single
agent or in combination with other agents) is the chemo drug most actively used today, as can be seen, the clinical
results with several hundred patients reflect palliation only, brief durations
of response, and no survival benefit even among those who initially respond. TAXOL (Paclitaxel) From 1997 to 2000 there
were 7 reviewable trials (Table 2) with 100+ patients reported. The Q weekly trials were all in combination
with Emcyt and resulted in reported RR of 60-85%; MDR of 5-9 months; and no
reported MDS statistics. There were
also partially reported combinations with VP-16 and Carboplatin. Taxol is a widely used agent in most types
of cancer, but seems to be declining in use for prostate cancer and replaced by
Taxotere. An interesting study found
that ‘...taxotere is capable of inducing...apoptotic cell death at 100-fold
lower concentrations than taxol.’ (Haldar et al.,Cancer Res 1997 Jan
15;57(2):229-33) EMCYT (Estramustine
phosphate) Emcyt is used as a
pharmacokinetic agent with many other chemo agents. It binds to microtubule-associated proteins to inhibit
microtubule organization and is synergistic with other microtubule
inhibitors. The precise mechanization
of Emcyt is unknown, but it does not directly damage DNA. But, Emcyt is hard on all aspects of body functions
and is responsible for considerable discomfort and forces cessation of treatments
due to toxicity. The enclosed 6 abstracts in
Table 3 (several more Emcyt inclusive abstracts appear with other agents) are
revealing--4 of them address oral Emcyt combined with oral VP-16 and reflect
better RR (39-78%), MDR (7 mos-208 days), MDS (13 mos->2 years) than most of
the other clinical trial abstracts. NOVANTRONE (Mitoxantrone) Novantrone is an old agent
that seems to be making another revival in the treatment of HRPC. See Table 4 where three single agent (with
Prednisone) trials in 99/00 with 300 patients recorded mixed results(enclosed):
RR in general were reported as ‘decreasing PSA’ and no reported MDR or
MDS. Other trials combined Novantrone
with 5-FU (RR 41%; MDR 4.7 mos.; MDS 11.5 mos.), SR 89 (no results reported),
VP-16 (10 pts.--RR 63% had 75% decrease in PSA), Novantrone + Taxol + Emcyt (RR
63%; MDR 9 mos.; no reported MDS). There are some new
randomized trials recruiting that will compare Taxotere + Emcyt with Novantrone
+ Prednisone and the N+P protocol is being actively suggested to HRPC patients
as a follow-on therapy after exhausting some version of Taxotere single agent
or Taxotere + Emcyt. In general, the RR
are no better than other widely used protocols, but the alternative therapy
might result in another brief respite from disease progression. ADRIAMYCIN (Doxorubicin) Adriamycin is an old chemo
drug used at some time in treating most forms of cancer. Only one prospective trial was reported in
2000. Adriamycin (‘...is known to have
activity...’) was combined with Navelbine (Vinorelbine), (‘...has been shown to
have efficacy in breast cancer...’) and Prednisone--Q 21 days. The trial reported only that ‘Substantial
benefit was seen in terms of decreased pain and increased QOL.’ This trial was obviously designed with the
new paradigm emphasis on palliative treatment of HRPC. (ASCO/00 1482) Adriamycin is often
discussed in the context of the ‘Logothetis Protocol’ (recruited in 1996) which
follows the 1997 update of the National Comprehensive Cancer Network (NCCN) guidelines
for the treatment of HRPC (the new paradigm).
The ‘Logothetis Protocol’ and the Kansas City Clinical Oncology Program
DM 97-022 are similar complicated alternating chemo therapies: Logothetis
combines Adriamycin + HDK + Vinblastine (Velban) + Emcyt on varying schedules
for 8 week cycles---the Kansas City trial combined Taxol + Emcyt + VP-16 for
group A; and Adriamycin + HDK + Vinblastine (Velban) + Emcyt for group B. The Logothetis protocol results were reported
as 67% RR in 46 patients for a minimum of 8 weeks; MDR 8.4 months; and MDS 19
months. (Clin Cancer Res 1997 Dec;(12 pt 1):2371-76) These results are not much better than
less toxic combinations and beg the question of whether HDK alone was
responsible for the response. SURAMIN Suramin has long been used
as treatment for several cancer types.
In general, it is considered to have ‘significant anti-tumor activity’. Several trials have been conducted on
HRPC---1.) Myers et al (J clin Oncolo. 1992;10:881-889) used a
continuous 7 day infusion of 350 mg/m2/day with 30% having a PSA decrease of
75%, MDR 26.3 wks., MDS 42.3 wks.;
2.) Eisenberger et al. (J
Natnl Cancer Inst. 1993;85:611-621) in varying doses; RR 80% and 83%
decrease in pain.; 3.) Tu et al. (Proc
Ann Meet Am Soc Clin Oncol 1997;16:A1239) gave various doses of Suramin by
IV bolus/2 hrs 2Xwk + Adriamycin (20 mg/m2); RR 52%; established the maximum
tolerable dose at 150-200 microg/ml.; 4.) Long et al. (Proc Annu Meet Am Soc
Clin Oncol 1997;16:A855) stated as a preamble ‘Suramin has shown significant
antitumor activity against HRPC.’; Suramin was given 5 days @ 300
microg/ml followed by 5 days of Topotecan (various doses)--Q28 days; RR 33%,
but 66% had progression of disease on a bone scan; 5.) ASCO/00 1332 reported 56 pts received multi-dose
(3)/42 days; 61% RR; MDR 4 mos.;
6.) ASCO/00 1291 reported 3 doses Q 28 days; RR 42% (low
dose), 48% (intermediate), and 58% (high-7.66 gm/m2 4/28 days); with MDS of
14.7 mos. (low), 13.2 mos. (intermediate), and 12.9 mos. (high); and, 6.) Small et al. (J Clin Oncol 2000
Apr;18(7):1440-50) conducted a double blind comparison or Suramin + HC vs
Placebo + HC; conclusions--Suramin + HC ‘...provides moderate palliative
benefit and delay in disease progression...’. Kelly et al. (Cancer, 1973)
reported a prospective study where HRPC patients were first treated with
Hydrocortisone and then with Suramin.
Only 10% of the patients received additional benefits from the Suramin. Hussain et al. (J Clin Oncol, Vol 18, No
5(March), 2000: pp 1043-1049) concluded that Suramin + hydrocortisone and
androgen deprivation has limited applicability in the treatment of patients
with newly diagnosed metastatic prostate cancer. Suramin has been
continually re-visited for several years in most conceivable combinations with
confusing results. Is Suramin dead for
a while? VP-16 (Etoposide) VP-16 is a relatively new
drug used for PCa and several other cancers.
It appears to work by cutting off the ends of chromosomes (telomere).
VP-16 has a potentially very serious after-effect---in approximately 5%
of patients it causes chromosomal defects that can lead to secondary cancers of
the bladder and other leukemias, and these secondary cancers are normally
fatal. Several clinical trials
used VP-16 as pharmacokinetic agents and the results are summarized in the
discussions of the taxanes (Taxotere and Taxol). Of interest are the four trials reported where Emcyt and VP-16
were administered orally with better success than most of the other
combinations. NAVELBINE (Vinorelbine) When combined with Emcyt,
one study reported a 56% RR for a MDR of 7 months (J Uro, Vol 17);
another combination with Emcyt (ASCO 1436/00) had a 50% RR with 21
patients and a MDR of 7 months. When
combined with Novantrone, a 37% RR occurred (ASCO 1240/99). When combined with Adriamycin (ASCO
1482/00) in 19 patients--RR of 31% and two patients still responding at 8
and 13 months; “Substantial benefit was seen in terms of decreased pain and
increased QOL.” Combined with Emcyt (ASCO
1480/00) ‘most’ of the 22 patients showed a RR, but there were two toxic
deaths. Navelbine as a single agent (ASCO
1453/00) at 30 mg/m2 IV on days 1 and 8 Q21 reported a 16.7 % RR. Weekly Navelbine + Emcyt resulted in a RR of
71%, MDR 16 weeks--‘The toxicity of short duration Emcyt is still
problematic.’ As a single agent (ASCO
1236/99) at 25 mg/m2/week, a RR of 40%, MDR 11.7 weeks, and MDR of 32
weeks. VELBAN (Vinblastine) Velban prevents cancer
cells from dividing by affecting the rods that form the cell’s skeleton. No clinical trials have been reported in
recent years but Velban is a component in the Kansas City program DM 97-022 and
in the Logothetis protocol (see Adriamycin--above). 5-FU (Flouracil) 5-FU is available as an IV
or as capsules and it blocks a protein that cancer cells require to copy and
repair their DNA. The agent is used in
many types of cancer treatments. There
were no clinical trials in recent reports using 5-FU in prostate cancer
treatments, but some medical oncologists are suggesting its use with the
Taxanes. CYTOXAN
(Cyclophosphamide) Cytoxan is often-studied as an agent for the treatment of PCa (PCRI - Sept 1997; See the writeup at the following url: http://www.prostate-cancer.org/education/andind/cytoxan.html Dr. Strum reports a trial of HDK with oral Cytoxan had a RR of 78% and
an MDR of 9 months (Proc Am Soc Clin Oncol:15:A698, 1996); and another
study of Cytoxan at 600-800 mg/m2/wk for four weeks + DPPE (a histamine antagonist)
wherein 20 patients had a 50% RR (J Clin Oncol 13:1398-403, 1995). In 1997 Dr. Strum concluded that “Cytoxan is
an extremely active chemotherapeutic agent for the treatment of prostate
cancer.” The Lupus Foundation of
America, Inc. states that Cytoxan is a dangerous drug because patients ‘...have
an increased risk of developing malignancies including leukemia, bladder
cancer, and other tumors.’ as a long term result of the use of the drug. However, there are some medical oncologists
that are combining Cytoxan with Adriamycin as salvage therapies following
failure of other more common treatments. Cytoxan is a
‘high-response’ agent in prostate cancer.
When combined with Adriamycin @ 40 mg/m2 + G-CSF Small et al. (JCO
14;1617-25, 1996) reported a RR of 46% and MDS of 23 months. Pavilck et al. (Proc. Am. Clin.
Oncol.;15A698, 1996) combined Cytoxan @ 100 mg/m2 orally/14 days; cycle 28
days with HDK for a 78% RR and 9 month MDR.
The Servadio
protocol has been used since 1980 in Israel with a cumulative survival rate of
55.5%. This protocol is often mentioned
but seldom utilized. Why? Servadio, Nissenkorn, Mukamel first reported
the concept in 1980 (Urology 1980 Sep;16(3):257-60) combining orchiectomy
+ DES (3 mg/day) + Cytoxan + 5-FU (10 mg/kg X 2 years; then 5 mg/kg X 2 years);
50% tumor shrinkage in 84% of patients; cumulative survival rate during 3.5
years was 76.5%. Servadio et al. again
reported in Urology 1983 May;21(5):493-5 of 24 Stage D patients
and the same hormonal/chemotherapy protocol a 79.1% tumor shrinkage,
stabilization/partial disappearance of osteoblastic lesions; cumulative
survival rates at 5 and 6 years were 63.48 and 50.78 %, respectively. Servadio again reported in Urology 1987
Oct;30(4):352-5 of 36 D2 patients on the same protocol; 75% had bone pain
relief; 80% had urinary symptom relief; 82.2% regression or stabilization of
the primary tumor; 55.5% stabilization/disappearance of osteoclastic lesions; cumulative
survival rate at 11 years is 55.5%. Again in 1992, Servadio et al. reported in Urology 1992
Mar;39(3):274-6 a retrospective 15 year review of his protocol of
hormonotherapy: 50 D2 patients treated on diagnosis; 28% died of the disease;
28% died of other causes; 40% are still alive (14% with clinical disease); he
suggests continuation of the protocol utilizing the newer chemotherapeutic
agents. The Servadio
protocol is well documented and represents the longest survival
statistics. Servadio continually
reports that this early aggressive combined systemic therapy intervention in D2
patients is well tolerated with only minimal temporary side effects. One wonders why it has not been investigated
and utilized in the U.S. Servadio began
his protocol on diagnosis of D2 with an orchiectomy, but with the advent of
Lupron/Zoladex, this would no longer be a necessity and the chemotherapy agents
combined in the protocol are well-known and in multiple use in other
pharmacokinetic combinations. Dr. Strum
suggests that the Servadio protocol is ‘over-treatment’ since perhaps surgical
or medical castration alone might provide similar survival, but this patient
suggests that the Servadio protocol results are well documented, while other
theories are not. CARBOPLATIN A standard PCa treatment of
the past few years has been Taxol + Emcyt + Carboplatin (see Taxol--ASCO
1364/00), but the trend has been away from Carboplatin because of permanent
neuropathy and toxicity. One study of
Novantrone at 8 mg/m2 IV + Carboplatin at AUC 4.5 IV + Prednisone--Q21 days
with 37 patients had a palliative response of 30%, a RR of 24%, and a
MDR of 8.3 months but concluded that this combination activity ‘...is unlikely
to be substantially greater than that of Novantrone + Prednisone...’ (ASCO
1455/00). Another study combined
Taxotere at 60 mg/m2 on day 2 + Carboplatin at AUC=5 on day 2 + Emcyt at 140 mg
po tid/days 1-5; 11 patients are in the trial and recruitment continues for 30
more patients. This trial’s preamble
stated ‘Chemotherapy has been associated with disappointing results in HRPCA
until recently when use of taxanes in combination with other agents has shown
response rates in excess of 60% based on a post treatment PSA decline of
>50% from pre-treatment values.’ (ASCO
1392/2000) NOTE: I am not a
doctor and can not give medical advice.
I am not a medical researcher. I
am a prostate cancer patient and I performed this layman’s analysis for my own
decision-making purposes. In
conjunction with a medical team, every cancer patient must make their own
decisions regarding treatment options.
I make no claim that this analysis is definitive or complete. Every HRPC
patient should thoroughly review the Life Extension Foundation’s web site
www.lef.org Prostate Cancer-Late
Stage. I invite any and all
additive contributions that will provide patients a framework which will
enhance their ability to make informed decisions regarding the use of
chemotherapy protocols in their struggle with prostate cancer. There are many innovative chemotherapy agent
combinations and protocols currently being investigated. How can we remain updated regarding the
latest innovations? August 2000
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