The present invention is a method of treatment for a patient with
cancer. In particular, it is a method of treating patients having
breast cancer using the microtubule agent, Taxol. The present method
of administration, serves to prevent or retard the adverse side
effects associated with Taxol and reduces the chances of a patient
developing mdr Taxol resistance. The novel method of treatment provides
a low-dose, longterm exposure to Taxol in a patient.
1. A method of treating a patient suffering from breast cancer,
(a) intravenously infusing taxol into said patient at a continuous
dosage rate of between 17.5 to 35 milligrams of taxol per square
meter of patient surface area per 24 hours to infuse between 70
and 140 milligrams of taxol per square meter of patient surface
area into said patient over a period of 96 hours; and
(b) repeating said step (a) in 21 day cycles until remission of
said patient's breast cancer is obtained.
FIELD OF THE INVENTION
The present invention relates to a method of treating patients
who have breast cancer.
More particularly, the invention relates to treatment of patients
with a taxol solution administered as a 96 hour continuous infusion
every 21 days.
BACKGROUND OF THE INVENTION
Taxol is a microtubule agent isolated from the stem bark of Taxus
brevifolia, the western (Pacific) yew tree. Taxol acts by promoting
the formation of unusually stable microtubules, inhibiting the normal
dynamic reorganization of the microtubule network required for mitosis
and cell proliferation (Schiff, P. B., et al. (1979) Nature 277,
665; Schiff, P. B., et al. (1981) Biochemistry 20, 3247). In the
presence of Taxol, the concentration of tubulin required for polymerization
is significantly lowered; microtubule assembly occurs without GTP
and at low temperatures, and the microtubules formed are more stable
to depolymerization by dilution, calcium, cold, and inhibitory drugs.
Taxol will reversibly bind to polymerized tubulin, and other tubulin-binding
drugs will still bind to tubulin even in the presence of Taxol.
Taxol interacts with the microtubule system of many types of organisms.
For example, in mammalian cells a 50 Nm Taxol concentration usually
causes a significant increase in microtubule number, with changes
in cell shape and mitotic arrest in actively dividing cells. (Parness,
J., et al. (1982) Biochem. Biophys. Res. Commun. 105, 1082). These
perturbations of microtubule function caused by Taxol have a critical
impact on the cell because of the role played by microtubules in
cell motility, secretion, and cell division.
Taxol has been studied for its effect in combating tumor growth
in several clinical trials using a variety of administration schedules.
Severe allergic reactions have been observed following administration
of Taxol. However, it has been demonstrated that the incidence and
severity of allergic reactions is affected by the rate of Taxol
infusion (Weiss, R. B., et al. (1990) J. Clin. Oncol. 8, 1263).
Cardiac arrhythmias are associated with Taxol administration, and
like allergic reactions, their incidence is affected by the rate
of Taxol administration. Sinus bradycardia and Mobitz II arrhythmia
will develop in approximately 40% and 5% of patients, respectively,
beginning 4-6 hours after the start of a Taxol infusion, and continuing
for 4-8 hours after its completion. In most patients, the abnormal
rhythm is hemodynamically stable and does not require cardiac medications.
Additionally, it has been observed that the incidence of severe
cardiac events is low in patients receiving Taxol alone. Thus, infusion
times up to 24 hours have been used in treatment with Taxol to decrease
the incidence of toxicity and allergic reaction to the drug. Data
from these studies indicates that reversible myelosuppression is
the dose limiting toxicity, with significant peripheral neuropathy
observed at doses of 275 mg/M.sup.2 and greater. Other toxicities
include myalgia, mucositis, and alopecia.
Clinical studies of Taxol have been performed in a number of tumors
including acute leukemias, breast cancer, ovarian cancer and melanoma.
In one study of 34 patients with ovarian cancer treated with 250
mg/M.sup.2 Taxol as a 24 hour continuous infusion, there was a 21%
objective response rate (Enzig, A. I. (1990) Proc. AACR 31, 187).
The major toxicities were neutropenia and peripheral neuropathy.
Another study of 30 patients with melanoma treated with the same
dose and schedule of Taxol exhibited an objective response rate
of 13% (Enzig, A. I. (1988) Proc. ASCO 7, 249).
Rowinsky, E. K., et al. ((1989) Cancer Res. 49, 4640) describes
a phase I study of Taxol in 17 patients with refractory acute leukemia.
Taxol was administered as a 24 hour continuous infusion and escalated
from 200 to 390 mg/M.sup.2. Severe mucositis limited further dose
escalation, and other nonhematological effects included peripheral
neuropathy, alopecia, myalgias, arthralgias, nausea, vomiting, and
diarrhea. Based on this study, the maximum tolerated dose and recommended
phase II doses for Taxol were 390 and 315 mg/M.sup.2, respectively.
Nine patients had transient reductions in peripheral blood and bone
marrow blasts, and three patients had complete clearance of leukemia
for less than one month.
Two mechanisms of Taxol resistance have been identified in vitro.
In one type of cell, resistance is on the basis of drug efflux,
and like other multidrug-resistant (mdr) cell lines, it has increased
levels of membrane P-glycoproteins(s), and shows increased drug
efflux (Gupta, R. S. (1985) Cancer Treat. Rep. 69, 515). These cells
are also resistant to the vinca alkaloids, doxorubicin, and other
natural products, and resistance is reversible with calcium channel
blockers such as verapamil (Racker, E., et al. (1986) Cancer Treat.
Rep. 70, 275). Another mechanism of resistance found in other taxol-resistant
cells involves mutations in the alpha- or beta-tubulin subunits,
with some of these cell lines actually requiring taxol for growth
and mitotic spindle formation (Schibler, M. J., et al. (1986) J.
Cell Biol. 102, 1522).
A potentially important factor in the area of Taxol research involves
the multidrug resistant gene (mdr). The product of this gene, called
the p170 glycoprotein, has been demonstrated in vitro to play a
role in resistance of tumor cells to Taxol. It has been demonstrated
that p170 functions as a membrane pump which actively transports
intracellular drug out of the cell. Using in vitro cell models,
several classes of drugs have been identified which block the action
of p170, including cyclosporin A, calcium channel blockers, phenothiazines,
and anti-arrhythmic drugs such as quinidine and amiodarone. These
drugs have been shown to reverse mdr-induced drug resistance by
increasing intracellular drug concentrations.
Investigators have found increased expression of mdr in a variety
of tumor types, including lymphoma and breast cancer. For example,
Goldstein, L. J., et al. ((1989) J. Nat'l Com. Inst. 81, 116) reports
moderately increased mdr expression in 22% (4/18) of untreated lymphomas
and in 60% (3/5) of treated lymphomas. Although it is unknown if
increased mdr expression is a clinically relevant mechanism of drug
resistance, there is in vitro evidence that mdr plays a role in
drug resistance to Taxol.
Although it is clinically unknown whether Taxol, an antimicrotubule
agent effective in the treatment of cancer, is less effective in
cells expressing the mdr gene, in vitro data shows that this is
a concern. Furthermore, no one has been able to demonstrate an effective
regimen for treatment of lymphomas and breast cancer which overcomes
the problem of mdr drug resistance. The present invention discloses
a method of treating breast cancer with a low-dose long term exposure
to Taxol. There is clinical and laboratory evidence that long infusion
times, on the order of 72-96 hours, may enhance the activity of
drugs, such as Taxol, which are transported by P-glycoprotein. (Lai,
G. M., et al. (1991) Int. J. Cancer, 49, 696). Thus the method of
the present invention is to administer taxol as a 96 hour infusion
in patients with breast cancer, to effectively treat the disease
and potentially reduce the chances of developing mdr Taxol resistance.
Accordingly, an object of this invention is to provide a method
of Taxol treatment effective against breast cancer.
An additional object of this invention is to provide a method of
Taxol treatment which reduces or eliminates the development of mdr
SUMMARY OF INVENTION
In accordance with these and other objects of the present invention,
a method of treating breast cancer with Taxol, with a reduced chance
of developing mdr Taxol resistances is provided which comprises
administration of Taxol as a 96 hour continuous infusion with a
dose level of between 70 and 140 mg/M.sup.2 /96 hours, the dose
level being dependent on the toxicity of Taxol on the patient.
This method provides an effective way of treating breast cancer
with Taxol. Additionally, because of the low-dose prolonged exposure
regimen, the chance of a patient developing mdr Taxol resistance
and other adverse reactions is potentially reduced.
DETAILED DESCRIPTION OF THE INVENTION
For the practice of one embodiment of the present invention one
must first prepare the Taxol solution. Taxol is supplied through
CTEP, DCT, NCI (IND#22850) as a concentrated solution, 6 mg/ml,
in 5 ml vials (30 mg/vial) in a polyoxyethylated castor oil (Cremophor
EL.RTM.) 50% and dehydrated alcohol, USP (50%) vehicle. The intact
vials should be stored under refrigeration and diluted prior to
use. When diluted in either 5% Dextrose Injection or 0.9% Sodium
Chloride, Taxol concentrations of 0.3-1.2 mg/ml are physically and
chemically stable for at least 12 hours at room temperature. (NCI
Investigational Drugs; Pharmaceutical Data (1990)). It has also
been demonstrated that Taxol concentrations of 0.6 mg/ml diluted
in either D5W or NS and 1.2 mg/ml diluted in NS prepared in polyolefin
containers are stable for at least 25 hours at ambient temperatures
(20.degree.-23.degree. C.). (Waugh, et al. (1990) Am. J. Hosp. Pharm.
All solutions of Taxol exhibit a slight haziness directly proportional
to the concentrations of drug and time elapsed after preparation.
Formulation of a small number of fibers in the solution (within
acceptable limits established by the USP Particulate Matter Test
for LVP's) has been observed after preparation of Taxol infusion
solutions. While particulate formation does not indicate loss of
drug potency, solutions exhibiting excessive particulate matter
formation should not be used. Therefore, in-line filtration may
be necessary and can be accomplished by incorporating a hydrophilic,
microporous filter with a pore size no greater than 0.22 microns
(IVEX-HP In Line Filter Set-SL, 15", Abbott model #4525 or
equivalent) into the fluid pathway distal to the infusion pump.
Taxol must be prepared in non plasticized solution containers (e.g.,
glass, polyolefin, or polypropylene) due to leaching of diethylhexylphthlalate
(DEHP) plasticizer from polyvinyl chloride (PVC) bags and intravenous
tubing. Taxol must not be administered through PVC intravenous sets.
Therefore, polyolefin- or polyethylene-line sets, such as IV nitroglycerin
sets (or equivalent) should be used to connect the bottle or bag
(containing the Taxol infusion solution) to the IV pump, a 0.22
micron filter is then attached to the IV set, and then may be directly
attached to the patient's central access device. If necessary, a
polyolefin-line extension set (Polyfin.TM. Extension Set, MiniMed
Technologies, Model #126) can be used to provide additional distance
between the IV pump and the patient's central access device.
To practice the invention, the final infusion solution may be prepared
by diluting the total daily Taxol dose (i.e., a 24 hour supply)
in 250 or 500 ml of 5% Dextrose Injection, USP or 0.9% Sodium Chloride
Injection, USP in either a glass, polyolefin or polypropylene container.
Each bottle will be infused over 24 hours via an infusion control
device. A total of four (4) bags/bottles are required for each 96
hour infusion. Each bottle should be prepared immediately prior
to use such that no more than 25 hours will elapse from the time
of preparation until the end of the infusion for each bag/bottle.
As described above, a polyolefin- or polyethylene-line set should
be used to connect the bag/bottle to the IV pump, followed by the
in-line filter which will be directly attached to the patient's
central access device.
The method of an embodiment of the present invention involves administration
of Taxol infusion solution as a 96 hour continuous intravenous infusion.
The Taxol solution is delivered through a permanent central intravenous
catheter, with cycles repeated every 21 days. Therefore, before
starting the therapy, patients must have a permanent or temporary
central venous access.
Because of the possibility of anaphylactoid reactions, a physician
should be readily available during the first 30 minutes of each
infusion, and IV epinephrine, hydrocortisone, and diphenhydramine
should also be kept available. However, because of the prolonged
96 hour infusion, a very low incidence of reactions is anticipated.
The following example illustrates a preferred embodiment of the
present invention, but should not be used to limit its scope.
The following criteria are used to measure the response to Taxol
treatment using an embodiment of the present invention:
Partial Remission (PR): Greater than 50% decrease in the sum of
the products of the diameters of all measurable lesions for at least
Minor Remission (MR): 25 to 50% decrease in the sum of the products
of the diameters of all measurable lesions for at least one month.
Progressive Disease (PD): 25% or greater progression in the sum
of the products of the diameter of any measurable lesion over one
cycle of chemotherapy or the appearance or any new lesion consistent
with metastatic disease.
Taxol was obtained as a concentrated solution, 6 mg/ml, in 5 ml
vials (30 mg/vial) in 50% polyoxyethylated castor oil and 50% dehydrated
alcohol. The Taxol was then diluted in 500 ml 5% Dextrose, to a
concentration sufficient to supply between 17.5 and 35 mg of Taxol
per square meter (based on the body surface area of the patient)
over a 24 hour period. The Taxol infusion preparation was prepared
between 30 and 60 minutes prior to beginning each 24 hour infusion.
The Taxol infusion solution was prepared in a polypropylene lined
semi-rigid container, in a volume of 500 ml.
The container [bag] with the Taxol infusion solution was connected
to an IV pump via a polyethylene tube An IVEX-HP In Line Filter
Set-SL, 15", Abbott model #4525 with a pore size of 0.22 microns
was then attached to the IV pump via a polyethylene line-tubing.
The in-line filter was then connected to the subjects central access
The Taxol solution was infused over a 24 hour period, controlled
by the IV pump. The procedure was repeated three more times, for
a total 96 hour continuous infusion. The final dose was between
70 and 140 mg/M.sup.2 /96 hours.
Twenty-three patients (11 breast, 2 Hodgkin's disease (HD), 4 mycosis
fungoides (MF) and 6 non-Hodgkin's lymphoma (NHL)) were treated
with the Taxol solution at the above-described rate of between 70
and 140 mg/M.sup.2 /96 hrs. This 96 hr continuous infusion was repeated
every 21 days, while patients were monitored for a response after
every two cycles. If a patient exhibited a toxic or allergic reaction
to a dose of Taxol, the dosage was lowered until tolerated. The
cycles were continued until a patient exhibited disease progression
or was stable for 4-6 cycles. All breast cancer patients had received
a doxorubicin or mitoxantrone containing regimen for metastatic
disease. Seven of these patients failed to respond, while the other
four responded but did not achieve complete remission. All of the
lymphoma patients failed to respond to multiple regimens within
6 months of receiving Taxol.
After treatment of the patients with the above-described Taxol
infusion solution at a rate of between 70 and 140 mg/M.sup.2 /96
hrs, every 21 days, patients were observed for response after every
two cycles. In the breast cancer group, 9 out of the 11 patients
exhibited a positive response (7 PR, 2 MR) to the treatment, for
a 82% total response rate. The seven of eleven (64%) partial remission
rate achieved in breast cancer patients is highly favorable over
the 33% response rate reported for a 24 hour infusion at 250 mg/M.sup.2
in a similar patient group. (Holmes, F. A., et al. (1991) Int'l
Nat'l Cancer Inst. 83, 1797).
Among the lymphoma patients treated, Taxol was active in 4 out
of 6 patients (3 PR, 1 MR) with diffuse large cell lymphoma. No
prior treatment of lymphoma with Taxol has been reported. The 50%
partial remission rate is favorable compared to the response rates
determined for Taxol treatment of other cancer types.
The invention has been described in detail with particular reference
to a preferred embodiment thereof, but it will be understood that
the invention is capable of other and different embodiments. As
is readily apparent to those skilled in the art, variations and
modifications can be affected within the spirit and scope of the
invention. Accordingly, the foregoing disclosure and description
are for illustrative purposes only, and do not in any way limit
the invention, which is defined only by the claims.