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Can Chemotherapy Extend Survival for Hormone Refractory
Prostate Cancer Patients?
A Patient’s suggestion that judicious selection and
sequencing of chemotherapy protocols can extend a quality life for HRPC
patients. February
2002 “It is sobering to note that the median survival of HRPC is less than one year, and no agent...has yet been shown to improve the median survival of such patients.” (40)----Isn’t it somewhat perversely satisfying to know that the Long White Coats (LWC) can be really wrong as they omnipotently forecast our deaths? SUMMARY Thousands of prostate
cancer chemotherapy trials and reports document a cohort of described patients,
the protocol of treatment with a chemotherapy agent or combinations of specific
agents, the response rate thereto, median duration of response, median duration
of survival, and occurrences of adverse side effects. All of the trial abstracts/reports conclude
that while the treatment was effective, no survival benefit resulted. Therefore, can we assume (and
it is sometimes stated) that these very expensive and debilitating treatments
are only palliative? HRPC chemo protocols report
median durations of survival of up to twenty-two months, but most are much
shorter. Therefore, are we to assume
that the average man in the treatment dies within a few months after beginning
the treatment? All of us know that when
a chemotherapy protocol is exhausted, or produced inadequate response, another
chemotherapy protocol is initiated. Yet,
I can find no reports or documentation of any semblance of suggested sequencing
of protocols. Rather, we are only
subjected to a specific suggestion of our medical oncologists for the next
treatment and he never presents/explains a matrix of available salvage
protocols for the patient to consider. (The best summary of the array of chemo treatments I have seen is
in LEF, pp. 607-615 = well worth studying.) I suggest that it is
incumbent on the patient to familiarize himself with all available protocols
and chemotherapy agents, even for his first entry into the chemotherapy world
of treatments. Most oncologists have
drug company relationships or personal experiences with particular chemotherapy
agents and either are not familiar with the matrix of offerings, or have no
interest in informing the patient of alternative agents/treatments. Also, most oncologists do not discuss
protocol response rates, median duration of response, median duration of
survival, or specific data regarding all of the side-effects resulting from the
agents/protocols. Again, I suggest that
it is incumbent on the patient to become as familiar as possible with the array
of treatments available and become an active participant with his medical team
in his treatment program ---and I suggest that a careful orchestration of
sequential chemotherapy treatments can prolong quality survival. Below, I have attempted to
present the major protocols and categorize them by response rates, median
duration of response, and median duration of survival. By proper sequencing the treatments, we could
expect to experience quality extended survival by virtue of responding to
each/some of the sequenced treatments? NOTE This is a summary update of
Chemotherapy - Part 1
and Chemotherapy - part 2.
To search my references: 1) for journals, go to the following URL --- http://www.ncbi.nlm.nih.gov/entrez/query/static/citmatch.html and follow the prompts; for the full-texts of the reports, go to your local hospital medical library and search the journals. 2) for the ASCO abstracts (there are no full-texts), go to the following http://www.asco.org/ac/1,1003,_12-002095,00.asp and click on search all abstracts. ACRONYMS AAWR –
Anti-Androgen Withdrawal Response. bid -- twice/day tid
-- three times/day Q21 -- every 21 days po
-- orally, by mouth PCa -- prostate cancer RR -- response rate = % of patients
that experienced >50% reduction in PSA MDR -- median
duration of response = months after TX start to disease progression. MDS -- median
duration of survival = months after TX start to death, OR LAST PATIENT
CONTACT. mg/m2 -- milligrams of agent per meter squared of skin
surface; easily calculated
by your doctor based on height and weight. DVT -- deep vein thrombosis
= blood clots. TX
-- treatment. DISCUSSION I propose the following
matrix as selection and sequencing of chemo protocols for HRPC as they relate
to effectiveness, side-effects, and patient
tolerance. I suggest that all HRPC
patients who are considering chemotherapy study the matrix, research the
abstracts/reports, and have open discussions with your oncologist regarding
each alternative protocol and its application in your particular case. If he/she does not have the
time or interest to discuss these with you, change medical teams. Assuming that the patient
has exhausted CHT (Casodex/Lupron, or equivalents),
AAWR (Flutamide or Casodex
withdrawal), H/LDK + HC, DES, or other estrogen treatments(e.g., Trans Dermal
Estrogen Patches) -- there are two
non-chemo (steroid) TXs that should be considered before chemo, or prolonging
time ‘off’ chemo should you respond to a chemo protocol (PSA <4.0) and elect
intermittent chemo TX (I did not respond to either of these, but I was heavily-TXd before trying them): a) Low-dose dexamethasone
(Decadron) @ 0.5-2.0 mg/day reported a RR of 50 to
79%, MDR of 2-15 months, and substantial radiographic evidence of disease
regression. (1, 2, 3). b) Low-dose Prednisone @ 7-10 mg/day reported
significant palliation, 12-24% PSA ‘suppression’, and MDR of up to 4+ months.
(4,5,6,7) The sequential chemo
protocols I suggest that are effective to prolong quality survival are: 1) Weekly single agent Taxotere (docetaxel)--Taxotere is one of the taxanes (Taxol is the other)---the taxanes
‘freeze’ the cancer microtubule spindles and thus inhibit microtubule depolymerization, attenuate bcl-2 and bcl-xl
expression, and produce apoptosis (death).
“Interest has shifted to administration of docetaxel
on a weekly basis, which is associated with a more favorable safety profile
than the conventional every 3-week schedule” (8). This protocol has lower responses than those
that include Emcyt, but the safety/side-effect
profile is preferable. Recent studies
report RR of 41% (27% had a decrease of >80%), MDR 5.1 months (0.9-18.2) and
MDS of 9.4 months (1.6-18.2) (9); earlier reports reflect RR of 47% and
well-tolerated. Scholz MC et al reported
RR of 61%, MDR of 5.6 months. (10)
As my earlier referenced papers reflect, I responded for 17 months to
this protocol with a PSA nadir of 1.2. 2) If your schedule denies being in a chemo room
3 out of 4 weeks per month, Q21 single agent Taxotere
is a viable next alternative with acceptable toxicity profiles. Picus J
reported RR of 46% (20% had >80% PSA reduction), MDR of 9 months
(2-24), and MDS of 27 months with Taxotere @ 75
mg/m2. (11). Hussain A et al reported RR of 57% with
minimum toxicities; Q21 Taxotere @ 70 mg/m2. (12) As explained in my earlier papers, I elected
weekly Taxotere for the favorable toxicity profiles
and the antiangiogenic properties of the weekly protocol
vs. the ‘kill ‘em all’ approach of the Q21 protocols,
but responses and durations of response are similar for weekly or Q21 single
agent Taxotere. 3) If the single agent Taxotere protocols exhaust or responses are not acceptable,
Emcyt (estramustine)
can be added to the single agent Taxotere. Emcyt is nitrogen
mustard linked to estradiol with antimitotic
(anti-growth) properties; it binds to tubulin and
microtubule proteins and disrupts the nuclear matrix (it might also inhibit
p-glycoprotein, a multidrug resistance protein); it
has a half-life of 50-100 hours; as a single agent, Emcyt
has a 37% RR (13), but has “..more than
additive antitumor activity..” when combined with
other microtubule inhibitors (taxanes). (14) But, Emcyt has a
DVT potential of up to 25%, even with coumadin and INRs >2.0, and continues to be problematical as this
condition is serious and TX-limiting. However, results are
improved by adding Emcyt to Taxotere. “It can be concluded that prostatic
tumors are highly sensitive to chemotherapy and that a new threshold of antitumor activity has been inaugurated based on the
significant activity of docetaxel/estramustine in
patients with HRPC. Docetaxel
is one of the most active agents in this patient population...” (8) Copur MS
et al found weekly Taxotere + Emcyt RR of 76% (56% had >75% decrease), MDR of
13 months, and MDS of 18 months. (15)
Kosty MP et al reported RR 71.4%
(35% > 75% reduction in PSA). (16) An interesting report is Rajasenan KK et al, a study where ten(10) HRPC
patients exhausted Q21 Taxotere + Emcyt
(disease progression) and switched to weekly Taxotere
+ Emcyt with a renewed RR of 70% and concludes that
weekly Taxotere + Emcyt has
significant activity in HRPC patients who progress following Q21 (17).
This was a small trial, but this
switch-over result is interesting re sequential TXs. 4) The Q21 Taxotere
+ Emcyt protocols are the most
effective of all the chemo treatments for HRPC.
While there are numerous trials/reports regarding Q21 Taxotere + Emcyt, the milestone
reports are: (A.) Petrylak et al with
a RR of 75% (45% had >80% PSA reduction) and MDS had not been reached;
moreover, he introduces intermittent TXing if the PSA
reaches a nadir of <4.0; this report shows intermittent ‘off’ time of 14-28
weeks before successfully re-TXiing
with the protocol (18); he subsequently reported on the same cohort as a
RR of 82% and MDS of 22.8 months (but he questions the efficacy of adding Emcyt vs. the side-effects). (19); and (B.) Saverese DM et al later reported RR of
68% (57% had >75% PSA reduction), MDR 8-10 months, MDS of 20 months, and DVTs of 9%. Of
the multitude of chemo trials/TXs for HRPC, this
protocol documents superior response, efficacy, and toxicity profiles (with
adverse Emcyt reactions a continuing problem). 5) If either weekly or Q21 day Taxotere (+/- Emcyt) is exhausted, or there is no response, Taxol is a viable next alternative. As discussed in my earlier paper at Chemotherapy - part 2, while both taxanes prevent the mitotic spindle from being broken down by stabilizing the microtubule bundles, Taxotere has a 2-fold higher affinity for microtubles and is TXd at 1/2 the dose of Taxol; and, Taxotere has the advantage of reduced peripheral neuropathies, arthalgia (joint pain)/myalgia (muscular pain) syndrome. (20) Moreover, both taxanes have significant antiangiogenic activity (21) and resistance to one taxane does not necessarily convey resistance to the other. (22) Weekly single agent Taxol was found to have a 75% RR, MDR of 5.3 months (3-8),
and one year survival was 83%. (23) Madrueno
FD et al found this protocol resulted in 96% response on metastatic sites in BCa. (24)
Trivedi C et al reported weekly Taxol with a RR of 39%, with considerable toxicity.
(25) 6) If no/inadequate response to single agent
weekly Taxol, Emcyt can be
added. Weekly Taxol
+ Emcyt was reported by Singh H et
al to have a RR of 75%, MDR of 19.6 weeks, and several toxicities
(small number of patients and strange reporting). (26) Taneja S et al,
in a dose escalating study, reported @ 60 mg/m2 a RR of
70%, but in a small cohort of patients. (27) Another PH II trial had a 60% RR with this
protocol. (28) Again, another study found that 50% of patients had an
80% decline in PSA (strange, small study). (29) SUMMARY OF THE TAXANES --Taxol/Taxotere
protocols report the most effective, patient friendly treatments for HRPC. Considering the RR, MDR, MDS, and toxicity
profiles, I suggest the first protocol should be weekly (3/4) single agent Taxotere @ 25-35 mg/m2; followed by adding low-dose Emcyt; next try Q21 Taxotere w/
or w/o Emcyt; then switch to weekly Taxol @ 50-70 mg/m2-- and, add Emcyt
if no/inadequate response. If these are
exhausted or inadequate response results: 8) Add Emcyt to
weekly Adriamycin---Culine
S reported a 58% RR, MDR of 3 months, and a significant regression of
pain and soft-tissue disease. (31)
9) Add Cytoxan
to weekly Adriamycin ---Cytoxan is considered pharmacokinetic with Adriamycin; Small, in a Q21 study of Adriamycin + Cytoxan (+ C-GSF),
reported RR of 46% (26% had >75% PSA reduction); MDS of 11-23 months. (32) Cytoxan as a
single oral agent @ 50 mg/day is considered metronomic dosing (cytotoxic and antiangiogenic)
with a RR of 68% and MDR of 7 months. (33) Also, this Cytoxan
protocol might be considered as a stand-alone salvage TX, or as maintenance if
response to other protocols allow intermittent chemo treatments. In a fascinating (but
complicated) trial, Logothetis et al administered
2/3 cycles of the Logothetis protocol (34) as
introductory chemo---followed by a randomized continuation of: a) single agent
weekly Adriamycin (6 wks) w/RR 72%, MDR 7 months
(2.3-20.9), MDS 16.8 months (4.4-34.2) + HDK maintenance until progression; vs.
b) one SR 89 infusion followed by weekly Adriamycin
(6 weeks) w/RR 89%, MDR 13.9 months (4.2-26.1), MDS 27.1 months
(4.9-37.7)---read it again--this are astounding results from Adriamycin + SR 89---the conclusion is that this
protocol definitely improved overall survival. (35) SUMMARY OF ADRIAMYCIN --after exhausting Taxotere/Taxol,
I suggest: a) weekly Adriamycin
is a viable TX, b) then add oral CY @ 50 mg/day, c) then add Emcyt, d) or, Q21 Adriamycin + Cytoxan, d) the Logothetis
finding is fascinating and well worth exploring; maybe add SM 153 (more
effective than SR 89) to weekly Adriamycin? Multiple trials of Novantrone report RR of 34%, MDR 175 days (37); RR
4%, but 63% had ‘decreasing PSA’; RR 55% in newly DXd
patients (38); RR 48%, MDR 10.5 months in a Novantrone
+ Prednisone arm vs. RR 24%, MDR 3.8 months in Prednisone only arm (39);
one report said that Novantrone caused
‘...significant reduction in pain and suffering in approximately 30-40% of
patients with HRPC.’ (40); the benchmark report for Novantrone
is Tannock IF which reported a RR of
33% (5% cardiac toxicity) and concludes the TX ‘...provides palliation for some
patients with symptomatic...’ HRPC (41); in a complicated study of 133
patients, RR 28% and palliative response of 38% (42); several additional
studies added various other chemo agents to the protocol and none had better
results than the basic TX. SUMMARY OF NOVANTRONE + PREDNISONE---while this TX is currently being pushed by oncologists, it only has a RR of about 33% and MDR of 5-10 months, and it is an anthracycline (as is Adriamycin); as such, it has serious side-effects of ‘...left ventricular dysfunction and myelosuppression.’ (destroys bone marrow). (43) Also, since Prednisone alone offers a RR of up to 24% (4,5,6,7), Novantrone only adds thereto for an added 9% RR and no additional MDR? After exhausting Taxotere, this is my current TX (February, 2002)---after two TXs, my PSA is
stable at 29, but my WBC falls to 2.0 (low acceptable 4.2) and GRAN falls to
0.9 (no TX if below 2.0) after each TX, but returns to low acceptable by the
next TX = Novantrone hammers your bone marrow, and
often requires growth factors (Leukine/neupogen),
which have their own set of side-effect to deal with. 11) 5-FU (fluorouracil) --blocks a
protein that cancer cells need to copy and repair DNA; it is a really old drug
having been administered for 50 years in TXing bowel,
head/neck, breast cancer; it is bolus administered (single, large quantity in a
short period = squirted) via a cannula; but, within
minutes it is catabolized (inactivated); the plasma
half-life of 5-FU is 6-20 minutes; historically, response rates rarely exceed
20%; concurrent administration of leucovorin/eniluracil
is required to enhance the binding of 5-FU enzymes in the cancer cell, the
combination greatly increases the ACU (concentration x time curve) of the
effective availability of 5-FU in the body.
Because of these bioavailability problems, prodrugs
(an inert drug that becomes active only after it is transformed or metabolized
by the body = converted by liver and tumor enzymes) have been developed and
allow daily oral administration, thus ease of administration and assuring
continued drug exposure to the cancer cells. (44) The two common 5-FU
prodrugs are: Uftoral = UFT (tegafur-uracile)--Bristol Myers--- significantly increases
the tumor-to-serum and tumor-to-normal tissue 5-FU ratios (minimal affect on
normal cells); but, co-administration of leucovorin
is needed for additional biochemical modulation (this combination of oral UTF/leucovorin is Orzel).
(44) Several trials (colrectal cancer) of UTF report minimal responses of 9-25%
and MDR of 3.5 months. (44) BCa trials report a partial response of 55%, MDR 14 months
with 5-FU/eniluracil (45); RR 18%, MDR 23.6 weeks for 5-FU/eniluracil in
BCa (46); RR 17%, stable PCa
disease in 44% (47) Xeloda (capecitabine) --Hoffman LaRoche---an oral
5-FU prodrug that is selectively tumor and system
activated/converted in the cell to its toxic moiety by naturally produced
enzymes (thymidine phosphorylase
= TP)----it is completely unchanged in the GI tract and is cell cycle phase
specific--TP is higher in tumors than surrounding normal tissues and the
sequence of activating the liver and tumor enzymes provides tumor selectivity
and decreases toxicity to normal tissues (48)--the prodrug
yields substantially higher concentrations of 5-FU in tumors than in plasma or
normal tissues and 5-FU levels are much higher than those achieved by intraperitoneal (stomach lining) administration of 5-FU at
toxic levels. Xeloda is more effective at a wider dose range and has a
broader spectrum of antitumor activity than 5-FU or
UTF--- it has additional characteristics not found in 5-FU such as potent antimestatic and anticachectic
(weight loss and wasting). (49) Xeloda has high therapeutic potential in TXing cancer; the antitumor
activity of Xeloda is greater than those of 5-FU and
UTF and much safer, less toxic to the intestinal tract = higher therapeutic
indices. (50) I cannot find any
abstracts/reports re the use of Xeloda in PCa, but I know some men who are using it after exhaustion
of other TXs.
There are 32 Xeloda abstracts in ASCO 2001,
most of them re colorectal and pancreatic cancer and most combine the prodrug with other agents.
A 66% response was observed with Xeloda + Cisplatin in AGC (advanced gastric cancer) (51);
response of 21%, MDR 221 days in taxane-refactory BCa (52); 53.85% response, MDR 128 days in heavily
pre-TXd BCa (53);
28.3% response, MDR 161 days for advanced metastatic BCa (54); 66% tumor control and low toxicity in MBCa after failure of Adriamycin
and the taxanes (55); 56% response with Xeloda + Vinorelbine in MBCa (56); 50% response with weekly Taxotere in MBCa that had failed Adriamycin (57). The reason I got bogged
down in 5-FU and the prodrugs is that p2p has, on
several occasions, suggested 5-FU as a salvage after
exhaustion of Taxotere, and many women with
metastasized BCa are taking Xeloda
after failure of other chemo protocols. SUMMARY OF 5-FU/PRODRUGS---the statistics look promising for BCa and I believe these are worth considering as salvage
for exhausted PCa chemo protocols---I hope ASCO 2002
sheds some light on Xeloda for PCa. 12) SERVADIO re-visited---I
presented this question in my first chemo paper and still do not understand why
there are no reports or practice of this protocol in the US. The protocol is: orchiectomy
+ DES + Cytoxan (cyclophosamide)
+ 5-FU. 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 (58)
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 (59) 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 63.5 % and
50.78 %, respectively. Servadio again reported in (60) 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 (61) 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 US? 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. Why not administer Casodex/Lupron
+ DES @ 3 mg/day (or less + breast RT) + Cytoxan @
50-100 mg/day po + Xeloda?---this would be an easy all oral TX with minimal
side-effects? 13) MISCELLANEOUS POSSIBILITIES-- a) NAVELBINE (Vinorelbine)
---Navelbine is a semi-synthetic vinca alkaloid that interferes with microtubule assembly by
inhibiting mitosis (growth) through its interaction with tubulin. There are mixed results of trials; I reviewed
5 trials that had <25% response for Navelbine or N
+ Emcyt; while Navelbine as
a single agent seems less than adequate (MSKCC reports that for all single
agent chemo agents, median survival is only 7 months (62))-- Navelbine
+ Emcyt shows promise: RR 50%, MDR 7
months (5-8) (63); Q21 RR 53% + ‘most pts. in
3rd cycle (64); weekly Navelbine RR 65% (65);
weekly: RR 71%, MDR 16 weeks, but ‘toxicity of
oral EMP (Emcyt) is still problematic’ (66).
b) VP-16 (etoposide)---VP-16 is known as a topoisomerese
enzyme inhibitor; works by blocking the action of the enzyme; the job of this
enzyme is to untangle strands of DNA during cell division--failure to do so
results in cell death; the enzyme does this by temporarily causing breaks in
the strand to allow another strand to pass through; VP-16 prevents the enzyme
from completing this repair job and damages DNA. But, it has a rather serious complication in
that in 5% of patients, it causes chromosomal defects leading to leukemia,
usually fatal. Pienta
KJ has done most of the work re VP-16. VP-16 has minimal activity
as a single agent (67); VP-16 + Emcyt
(both oral) had RR of 50% (>75% PSA reduction in 28%), RR 58% in pts. with
bone disease (68); RR 39%, MDS 56 weeks (69); RR 45% in
soft tissue and 58% in bone disease, MDS 13 months for both arms (70);
RR 45%, MDS 32 months (71); Q21 RR 50%, MDS 208 days (71-693). (72) Therefore, VP-16 + Emcyt seems to be a viable first-line or salvage TX
with RR of 50% with MDS of about 1 year. c) Velban
(vinblastine)---an old drug that inhibits
microtubule assembly--Velban + Emcyt RR 40% PSA decrease of 25%, MDR 9 months, MDS
11.7 months (73); randomized study: Velban
single agent MDR 2.1 months, MDS 9.2 months--Velban +
Emcyt MDR 3.7 months, MDS 11.9 months but with
significant toxicities in the Velban + Emcyt arm (74); an interesting study by Trudeau
Mg et al. found in newly DXd metastatic
PCa patients (75), Zoladex
+ Velban @ 4 mg/m2 weekly (6/8) + Emcyt
@ 10 mg/kg po daily X 6 weeks---RR 100% with
11/15 complete responses; toxicity was minimal. (75) Too good to be true? These patients were TXN1M0 or M1--(TX =
primary tumor cannot be assessed; N1 = mets in single
LN 2 cm or less; M0 = no distant mets; M1 = distant mets); no bone mets. February 2002 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? References
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