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Clinical Status and Optimal Use of Amifostine

Clinical Status and Optimal Use of Amifostine

ABSTRACT: Amifostine (Ethyol) is an analog of cysteamine that selectively protects normal tissues in multiple organ systems against the toxic effects of radiation and various cytotoxic drugs while preserving the antitumor effects of these therapies. Amifostine was evaluated in a multicenter, multinational phase III clinical trial that enrolled women with stage III/IV ovarian cancer. Its effects have also been studied using normal human bone marrow and human breast cancer cells, as well as leukemia cells. Additional clinical trials have shown that amifostine can protect normal tissues from the toxic effects of alkylating agents, organoplatinums, anthracyclines, taxanes, and radiation. Other laboratory and clinical investigations indicate a potential role for this cytoprotective agent in the treatment of the ineffective hematopoiesis characteristic of the myelodysplastic syndromes. [ONCOLOGY 1(13):47-58, 1999]

Introduction

The recent decline in mortality observed among
patients with cancer reflects not only improved methods for
prevention and early detection of malignancy but also better
treatments. The most striking therapeutic advances are the result of
improved surgical techniques combined with cytotoxic radiation and/or
drug therapy.

Historically, the notion of patients deriving potentially significant
benefit from cytotoxic therapy was disparaged because of the
presumption that cytotoxic therapies could not distinguish between
normal and neoplastic tissues. However, the degree and duration of
cytotoxic damage to normal and neoplastic tissue differ sufficiently
to allow for clinically meaningful benefits in the palliation and
cure of cancer. Whether the goal of therapy is palliation or cure
determines the degree of risk and cost that the patient and health
care system are willing to accept, since virtually all cytotoxic
therapies have a narrow therapeutic index. This toxicity to normal
organs not only limits the use and achievement of the full
therapeutic potential of cytotoxic agents but also claims a cost in
terms of patient morbidity and mortality.

Oncologists attempt to mitigate the toxic effects of chemotherapeutic
agents by adjusting the dose and frequency of treatment. A major
drawback to this strategy is insufficient control of the tumor. A
growing area for new drug development is the evolving field of
supportive care agents intended to avert or minimize
treatment-limiting toxicities to normal organs.

Historically, the oldest approach of this type was the use of rescue
agents, such as leucovorin “rescue” following high-dose
methotrexate.[1] This approach has been useful for the treatment of
pharmacologic sanctuaries, such as the central nervous system
(CNS),[2] as well as tumors that are relatively resistant to standard
doses of methotrexate, such as osteosarcoma. Likewise, the use of
marrow-stimulatory cytokines following moderately toxic doses of
drugs has been useful.

An alternate approach to rescue techniques is the use of
cytoprotective agents, or cytoprotectors. These drugs selectively
protect normal tissues from the cytotoxic effects of drugs and/or
radiation while preserving their antitumor effects. The ideal
cytoprotector should be easily administered and should have a broad
spectrum of activity; not only should it be able to protect multiple
tissues, but also it should protect these tissues from diverse
cytotoxic treatments. The agent also should have a reasonable safety
profile. By improving patient tolerability to the therapy, the
cytoprotector may provide multiple benefits: It may improve patient
quality of life; allow for dose-inten-sification and, thus, improved
response and/or cure rates; and decrease costs associated with other
supportive care measures needed to treat treatment complications.

To date, three cytoprotectors have been approved by international
regulatory agencies. Mesna (Mesnex) is approved for the protection of
the bladder from the toxicity associated with ifosfamide (Ifex) and
high-dose cyclophosphamide (Cytoxan, Neosar).[3] Dexrazoxane
(Zinecard) is used to protect the heart from the cardiomyopathy
associated with the cumulative cardiotoxic effects of doxorubicin.[4]
Both of these agents are drug- or drug class–specific and their
protective effect is limited to specific organs—the urinary
bladder for mesna and the heart for dexrazoxane.

Amifostine (WR-2721 [Ethyol]) is the first broad-spectrum
cytoprotective agent to be approved by international regulatory
agencies. In this context, broad spectrum refers to cytoprotection
against a broad array of cytotoxic therapies, ie, multiple drug
classes as well as radiation, in multiple organ systems. Laboratory
and clinical studies have shown that amifostine protects cells in
virtually all organ systems except the CNS, which is a target for
both acute and cumulative (or delayed) cytotoxic damage. Because of
poor tissue distribution pharmacokinetics in the CNS, this organ
system has not been effectively studied.

This article will review preclinical and clinical studies of
amifostine, as well as trials evaluating its chemoprotective and
radioprotective effects. Studies suggesting that amifostine
pretreatment may also enhance the antitumor effects of chemotherapy
in certain settings and prevent secondary malignancies are also detailed.

Preclinical and Early Clinical Trials

Amifostine was originally synthesized under a classified project of
the US Army aimed at developing agents to protect the military from
the effects of radiation from a nuclear warhead. (Its military code
name is WR [Walter Reed]-2721.) Amifostine was selected for further
development from over 4,000 compounds because of its superior
radioprotective and safety profile. The synthesis of this series of
sulfhydryl-containing compounds was based on previous observations
showing that the sulfhydryl-containing amino acid, cysteine[5] and,
subsequently, cysteamine could protect rodents from lethal doses of radiation.

Amifostine (Figure 1), an analog of
cysteamine, is a phosphorylated aminothiol prodrug that is
dephosphorylated in the tissues by membrane-bound alkaline
phosphatase to its active metabolite, WR-1065. A free thiol, WR-1065
is the form of the drug that is taken up into cells and is the major
cytoprotective metabolite. Oxidation of WR-1065 forms the symmetrical
disulfide, WR-33278, which not only is structurally similar to
spermine, a naturally occurring polyamine, but also shares certain
biochemical properties with the polyamines that may contribute to
some of its pharmacologic properties.

Pharmacokinetics

The selective cytoprotection of normal tissue by amifostine stems
from its unique systemic and tissue distribution pharmacokinetics.
Following intravenous administration of the drug, the half-lives of
both the distribution and elimination phases in humans are extremely
short (alpha-half-life, < 1 minute; beta-half-life, 8.8 minutes).
Most (90%) of the drug is cleared from the plasma within 6 minutes,
and only a small amount of the prodrug is bio-converted to the free
thiol in the systemic circulation relative to normal tissues.[6-9]

Generation of the free thiol, WR-1065, occurs primarily at the tissue
site due to local dephosporylation by membrane-bound alkaline
phosphatase; this enzyme has relatively high specific activity in the
endothelia of normal capillaries and membranes of normal cells but is
relatively deficient in the neovascular endothelia and membranes of
cancer cells.[10-12] Once inside the cells, WR-1065, the free thiol,
provides protection from cytotoxic damage by acting as a scavenger of
oxygen-free radicals generated by radiation[13] and
anthracyclines,[14] and by binding to highly reactive nucleophiles
that would otherwise cross-link and damage DNA.[15-17]

Recent studies suggest that amifostine or WR-1065 can up-regulate
gene expression of p53[18]; this results in cell-cycle accumulation
at the G1-S interface, which, in turn, may allow for more efficient
DNA repair. Extensive preclinical studies, in both cell cultures and
tumor-bearing rodents, have shown that amifostine selectively
protects normal tissues without protecting a wide variety of murine
and human carcinomas, sarcomas, and leukemias.[19]

Based on this preclinical profile, amifostine has been studied in a
number of clinical trials. The combined laboratory and clinical
experience to date has shown protection of the organs listed in
Table 1
from cytotoxic damage. As a result of these studies, an
expanded pharmacologic profile of amifostine is emerging (Table
2
). The following summary will provide a brief overview of these areas.

Studies of Chemoprotective Effects

Following extensive controlled laboratory investigations and a series
of phase I and II clinical trials, it was evident that pretreatment
with amifostine could protect normal tissues from hematologic
toxicity associated with cyclophosphamide (Cytoxan, Neosar) or
high-dose cisplatin (Platinol)[20,21] and from nonhematologic
toxicities associated with cisplatin, and that it could achieve this
cytoprotection without any negative effects on the antitumor efficacy
of these drugs.[20,22-24] Amifostine-mediated cytoprotection against
these hematologic and nonhematologic toxicities was evaluated in a
multicenter, multinational, phase III clinical trial that enrolled
women with stage III/IV ovarian cancer (Figure
2
). Following surgery for tumor debulking and staging, patients
were stratified based on residual tumor and cancer center and were
randomly assigned to receive six cycles of cyclophosphamide plus
cisplatin with or without amifostine, administered at 3-week intervals.

Prior to receiving any chemotherapy, all patients were hydrated with
5% dextrose in 0.45% saline (200 mL/h) for 6 hours. Patients were to
receive drug therapy only when urine output exceeded 150 mL/h for 3
hours. Patients also received mannitol diuresis. Amifostine, 910
mg/m², was administered as a 15-minute intravenous infusion to
patients in a supine position. Within 15 minutes of the completion of
the amifostine infusion, cyclophosphamide, 1,000 mg/m², was
administered over 20 minutes. Immediately following the
cyclophosphamide infusion, a 30-minute infusion of cisplatin, 100
mg/m², was administered.[22]

A total of 242 patients were enrolled in this ovarian cancer trial;
122 patients were randomized to receive amifostine and
cyclophosphamide-cisplatin chemotherapy, and 120 patients were
randomized to receive chemotherapy alone. The two treatment arms were
well-matched with respect to age, race, International Federation of
Obstetrics and Gynecology (FIGO) stage, extent of residual disease,
and performance status.[22] The clinical end points of the trial
included assessment of the expected toxicities—hematologic,
renal, peripheral neuropathy, and ototoxicity, as well as antitumor efficacy.

Hematologic Toxicity

The major hematologic end point was the cumulative incidence of
neutropenic events through the six cycles of therapy. Neutropenic
events were defined as grade 4 neutropenia with fever and/or signs
and symptoms of infection that usually require hospitalization,
clinical and laboratory evaluation, and institution of empiric
broad-spectrum antibiotic therapy.

Figure 3 shows the cumulative
incidence of neutropenic events in both treatment arms. Pretreatment
with amifostine resulted in a significant reduction in this
potentially life-threatening event. As shown in Table
3
, amifostine pretreatment significantly decreased all
parameters of hematologic toxicity. Most notably, it reduced both the
number of days the patient spent in the hospital and the cumulative
number of days of treatment with broad-spectrum antibiotics as a
consequence of neutropenic events.

Renal Toxicity

The protocol-defined renal end point to assess the ability of
amifostine to protect against cisplatin-induced nephrotoxicity was
the need to delay or discontinue cisplatin therapy because of
elevations in serum creatinine > 1.5 mg/dL. If serum creatinine
level was > 1.5 mg/dL at day 22, cisplatin was to be delayed for a
maximum of 2 weeks; if it remained at a level exceeding 1.5 mg/dL at
day 35 (defined as a protracted elevation of serum creatinine),
cisplatin was to be discontinued.

Figure 4 displays the proportion of
patients who met these criteria for a delay in or discontinuation of
cisplatin therapy. Consistent with the cumulative nature of
cisplatin-induced nephrotoxicity, by cycles 5 and 6 a significantly
greater proportion of patients in the control arm compared to the
amifostine arm could not receive cisplatin as scheduled because of
elevated serum creatinine levels. These differences were
statistically significant despite the fact that patients in both
groups received comparable doses of cisplatin (median cumulative
doses, 555 and 500 mg/m² for the amifostine and control groups, respectively).[22]

Since, in most hospitals, the upper limit of normal for serum
creatinine in women is 1.0 mg/dL, a rise in serum creatinine to 1.5
mg/dL would represent a substantial deterioration in renal
function.[25] Estimations of creatinine clearance utilizing serum
creatinine, age, weight, and gender were calculated utilizing the
formula of Cockcroft and Gault.[26] As shown in Table
4
, by the end of therapy, 33% of patients treated with
chemotherapy alone had a ³ 40%
reduction in creatinine clearance. This was reduced to 10% in the
amifostine-treated patients (P = .001).

The 33% incidence of a ³ 40%
reduction in creatinine clearance in the control arm of the ovarian
cancer trial is consistent with the incidence observed in women
treated with up to six cycles of the same regimen in a trial
conducted by the Southwest Oncology Group (SWOG).[27] In this trial,
after the last cycle of therapy, 40% of patients (51/127) sustained a ³
40% reduction in creatinine clearance from baseline. Similarly, in
two other trials that used single-agent cisplatin (100 mg/m2 for 5
monthly cycles) in previously untreated patients with advanced
ovarian cancer, a > 40% decrease in glomerular filtration rate, as
measured by endogenous creatinine clearance[28] or ethylene-dinitrilo
tetraacetic acid (EDTA) clearance,[29] was noted in 35% and 45% of
patients, respectively.[28,29]

Other reports have shown comparable cumulative nephrotoxic effects of
cisplatin, as measured by progressive increases in serum creatinine
values and progressive decreases in creatinine clearance measurements
through five or six cycles of cisplatin (80 to 100
mg/m²).[27,30-40] In contrast, in phase II clinical trials using
monthly courses of amifostine (740 or 910 mg/m²) prior to
cisplatin (120 mg/m²) in patients with non-small-cell lung
cancer (NSCLC), melanoma, breast, or head and neck cancer, the
frequency of a ³ 40% reduction in creatinine clearance from
baseline was 8%, which is consistent with the 10% incidence observed
in the amifostine arm of the ovarian cancer trial (Table
5
).[20,22,23,27]

The literature shows that the cumulative nature of cisplatin
nephrotoxicity is generally permanent. The data from the ovarian
cancer trial support this conclusion. The reduction in glomerular
filtration rate at the end of cisplatin therapy observed in the
control arm of that trial persisted through a 30-month follow-up
period (Figure 5). This loss in
renal reserve will have an impact on further antineoplastic and other
therapies that require renal elimination or that have intrinsic renal
toxicity—a clinical concern that also pertains to the use of
certain radiographic contrast agents.

Clinical Neurotoxicity

In the ovarian cancer trial, clinical neurotoxicity was scored in
accordance with the National Cancer Institute (NCI) grading system.
The higher grades include troublesome paresthesias and inability to
perform fine finger motions. Treatment with amifostine resulted in a
significant reduction in the severity of clinical neurotoxicity (Table
6
).

This is consistent with amifostine neuroprotection reported by
Mollman et al.[41] They found a 40% reduction in ototoxicity (defined
as troublesome tinnitus and clinical hearing loss requiring a dose
reduction or discontinuation of cisplatin) in the amifostine-treated
patients compared to the control patients, although the difference
was not statistically significant, as only 7% of control patients
experienced this toxicity.

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