19_08

Chapter 19: Pharmacology of Cancer Chemotherapy
19.8: Miscellaneous Chemotherapeutic Agents

Bruce D. Cheson

Cancer: Principles and Practice of Oncology, 6th Edition
Published by Lippincott Williams & Wilkins, Copyright 2001

Homoharringtonine

Homoharringtonine (HHT) and its congener, harringtonine, are
cephalotaxine esters isolated from the evergreen tree Cephalotaxus
fortunei Hook F, which is distributed throughout southern and
northeastern China. The two esters differ by only a single methylene
group, and they have similar activity against murine leukemia. [ref: 1]
The greater availability of HHT led to its further testing in the
United States.
The primary action of HHT appears to be inhibition of protein
synthesis, with degradation of polyribosomes, delayed inhibition of
initiation of protein synthesis, and inhibition of chain elongation by
interference with peptide bond formation. [ref: 2] DNA effects may also
be important, with a block in progression of cells from G(1) into S
phase and from G(2) phase into M phase. [ref: 3] Prolonged drug
exposure is necessary for maximal antileukemic effect in vitro.
Preclinical toxicology identified toxicities of the bone marrow,
gastrointestinal tract, kidneys, and heart. [ref: 4,5]
Radiolabeled HHT exhibits a triphasic plasma decay, with a terminal
half-life of 65.3 hours and an apparent volume of distribution of 2.4
L/kg. [ref: 6] In early phase I studies, HHT was administered as a
daily 10- to 360-minute infusion for up to 10 days. [ref: 7] Dose-
limiting cardiovascular toxicity with hypotension began 4 or more hours
after drug administration, which is presumed secondary to
vasodilatation with a compensatory increase in cardiac output.
Hypotension is ameliorated by interrupting the infusion or by fluid
administration, or both, and prolonging the duration of administration.
The major dose-limiting toxicity with currently used infusion schedules
is myelosuppression.
Initial clinical studies with HHT conducted in China identified
activity against acute myeloid leukemia and chronic-phase chronic
myelogenous leukemia (CML). [ref: 8] Clearing of central nervous system
blasts occurred after intrathecal administration. Variable activity was
observed in the initial series of phase II trials in U.S. pediatric and
adult patients with acute leukemia or myelodysplastic syndrome. [ref:
8-10] In late chronic-phase CML, a continuous intravenous infusion of
HHT, 2.5 mg/m**2/d, for 10 to 14 days each month induces complete
hematologic remission in 72% of cases, with cytogenetic response in
31%. [ref: 11] HHT is being combined with interferon or cytarabine in
early chronic-phase CML. O'Brien et al. [ref: 12] reported that HHT
followed by interferon did not achieve a higher cytogenetic response
rate than previously observed with HHT alone.
Nonmyelosuppressive toxicities have been minimal, including diarrhea,
hyperglycemia, nausea and vomiting, tachycardia, chest pain, headache,
and fatigue.

Suramin

Suramin is a polysulfonated napthylurea first used for the treatment of
onchocerciasis and trypanosomiasis in the 1920s. Its use against
parasites and discoid lupus erythematosus was abandoned because of the
availability of more effective drugs. Its inhibition of reverse
transcriptase and other RNA polymerases led to trials in patients with
autoimmune deficiency syndrome. [ref: 13] However, initial clinical
enthusiasm was not substantiated by additional study. [ref: 14,15]
The precise mechanism of suramin's antitumor action is unknown. The
drug binds nonspecifically to a wide variety of plasma proteins and
enzymes. It inhibits the binding and mitogenic action of many
polypeptide autocrine growth factors, including platelet-derived growth
factor, fibroblast growth factor, transforming growth factor-alpha and
-beta, epidermal growth factor, insulin-like growth factor-1 and -2,
interleukin-2, transferrin, and nerve growth factor. [ref: 16] It is
capable of dissociating growth factors from their receptors, with
higher affinity to heparin binding growth factors. It interferes with
glycosaminoglycan catabolism, leading to an accumulation in the liver
and blood of heparan sulfate and dermatan sulfate, which are thought to
be related to cell proliferation. Suppression of bone resorption may
contribute to the decreased pain reported in patients with prostate
cancer.
Suramin exhibits antitumor activity against a number of cell lines,
notably growth factor-responsive tumors, but low doses induce
proliferation in some cell lines. It inhibits the growth of malignant,
but not normal, prostate cells. Early clinical trials suggested
activity against adrenal, renal, and other cancers. [ref: 16] Activity
in prostate cancer has led to phase III studies.

Clinical Pharmacology

Suramin has limited absorption from the gastrointestinal tract. The
intravenous route is recommended because of better bioavailability.
The original dosing schedule of 1 g weekly for 6 weeks resulted in
plasma concentrations that fell over the first few hours after
administration but gradually increased over time, with increasing
trough levels before each injection. [ref: 17] The pharmacokinetics
were described by a two-compartment model, with an initial
(distribution) half life (t(1/2)alpha) of 2 days and an elimination
half life (t(1/2)beta) of 48 days (range, 44 to 54 days). Suramin is
99.7% protein bound, primarily to albumin, and may persist in the blood
for 3 months after administration, with no evidence of metabolism and
80% renal clearance. The total body clearance is only 0.41 mL/min, with
little interpatient variability. Suramin does not cross the blood-brain
barrier. It may displace other highly protein-bound drugs.

Dose and Schedule

The optimal schedule of administration is still being determined. [ref:
18-24] Earlier schedules used adaptive control feedback [ref: 25] in
which the timing and calculated dose were pharmacologically computed
for individual patients to maintain plasma concentrations in the range
of 200 to 300 ug/mL. Labor-intense pharmacologic monitoring was used
because of concern that the severe neurologic toxicity with suramin was
directly correlated with high blood levels. More recently, other
pharmacokinetic correlations have been postulated, including time above
a threshold concentration, total dose, and others. [ref: 26] The
relative importance of free drug concentration is unknown. However,
several phase I studies have determined that concentrations in the 200
to 300 ug/mL range are better tolerated overall. Phase I studies have
demonstrated little pharmacokinetic variability, making complex
adaptive control algorithms unnecessary. This observation has led to
investigation of a wide variety of schedules, including a 14-day
continuous infusion, intermittent short infusions, and intermittent
bolus administration. [ref: 20,27-29]
Suramin has modest activity in patients with prostate cancer. [ref:
19,27,28,30,31] Combinations with other agents have been studied in
prostate cancer and other solid tumors, but without clear additive
benefit. [ref: 32-37] The future of this drug is uncertain.

Toxicity

The most serious toxic effect of suramin is a polyneuropathy, which may
begin within several weeks of therapy and peaks in severity 3 to 6
months after the drug is discontinued. It ranges from mild stocking-
glove paresthesia to paralysis requiring mechanical ventilation, and it
is an indication to discontinue treatment. [ref: 38,39] At 350
mg/m**2/d by continuous infusion, a Guillain-Barre syndrome occurred in
11% of patients; the incidence increased to 40% with levels of more
than 350 ug/mL . [ref: 38] Suramin may lead to a progressive,
reversible myopathy; hyperesthesia of palms and soles; headache; and
altered taste. Adrenal insufficiency is very common and may be
irreversible. All patients receive concurrent corticosteroids until
normal adrenal function can be documented.
Infections are frequent with suramin therapy because the drug induces
lymphocytotoxicity and myelosuppression and inhibits phagocytosis and
bacterial killing, which is compounded by the addition of
hydrocortisone.
Other common toxicities include renal dysfunction, transaminase
elevations, and coagulopathy. [ref: 40,41] Prophylactic vitamin K has
been used to minimize the contribution from other causes. Bleeding is
managed by replacement of blood and plasma. Heparin can be given safely
using careful monitoring. An increase in serum creatinine or the
development of a coagulopathy necessitates interruption of therapy.
Other serious toxicities include supraventricular arrhythmias,
especially atrial fibrillation, pericardial effusions, and deep venous
thromboses.
Rash has been reported, occasionally with desquamation or toxic
epidermolysis as well as keratoacanthomas and superficial actinic
keratoses. Vortex keratopathy, which resolves after therapy, also has
been reported. Metabolic consequences include hyponatremia,
hypokalemia, hypocalcemia, hypermagnesemia, hypophosphatemia,
hypouricemia, and elevations in amylase and lipase. Rash and renal
dysfunction may not recur if the drug is resumed.

Bleomycin

The bleomycins are a group of glycopeptides originally extracted from a
strain of Streptomyces verticillus from culture broths obtained from
the soil of a Japanese coal mine. [ref: 42] The most active agent was a
mixture of peptides now known as bleomycin, with a molecular weight of
1200.
The primary action of bleomycin is to produce single- and double-
strand DNA breaks, which result from the production of free radicals by
an Fe(II)-bleomycin complex intercalated between opposing strands of
DNA. It is ineffective in producing strand breaks of native RNA or
synthetic ribonucleotide polymers. Cells are most sensitive to
bleomycin during the G(2) and M phases and least sensitive in the G(1)
phase. [ref: 43] Noncycling cells may be more sensitive than cycling
cells. The observation that cells were killed during G(2) suggested an
advantage for a continuous infusion, which was not supported by
clinical trials.

Cellular Pharmacology

Bleomycin is taken up by cells slowly and inactivated by an
aminohydrolase found in normal and malignant cells. [ref: 44] Hydrolase
levels are higher in animal species resistant to the pulmonary toxicity
of bleomycin and is low in lung and skin, the two organs most
susceptible to bleomycin toxicity. Levels in tumor cell lines do not
appear to correlate with drug resistance.

Clinical Pharmacology

Using a 4- to 5-day continuous intravenous infusion, the steady-state
concentration is approached approximately 12 hours after initiation of
infusion and ranged from 0.132 to 0.312 mu/mL. After an intravenous
bolus of 15 U/m**2, peak plasma concentrations reach 1 to 10 mu/mL,
with a rapid two-phase disappearance from plasma with a half-life of
elimination of approximately 3 hours. Approximately two-thirds of
excretion is renal, and the half-life increases rapidly in patients
with a creatinine clearance of less than 25 to 35 mL/min. There is
increased pulmonary toxicity with renal insufficiency, but no formal
guidelines for dose reduction have been determined. Bleomycin is
absorbed rapidly after intramuscular administration, resulting in peak
plasma concentrations approximately one-third to one-half of those
obtained after rapid intravenous administration. One hour after
intramuscular injection, maximum serum levels range from 0.13 to 0.35
mu/ml, with no drug detectable in the serum 24 hours after injection.
Absorption after subcutaneous injection has not been clearly defined.
Intracavitary administration of bleomycin achieves levels 10- to 22-
fold higher than simultaneous plasma levels and is effective in the
control of malignant effusions. [ref: 45-49] Approximately 45% of the
intracavitary dose is absorbed into systemic circulation. Bleomycin
also has been applied topically. [ref: 50] No pharmacologic advantage
to intraperitoneal administration has been reported.

Toxicity

A test dose of 1 mg of bleomycin is generally administered before a
weekly or twice-weekly dose of 5 to 15 U/m**2 because of the risk of
hypersensitivity with urticaria, periorbital edema, and bronchospasm.
The dose-limiting toxicity of bleomycin is pulmonary fibrosis of
uncertain pathogenesis, which occurs in 10% of patients and is more
common in patients older than 70 years, with doses of more than 400 U,
or in those with a history of chest radiotherapy and in the
postoperative period. [ref: 51-59] The onset is usually delayed, and
the initial physical examination and chest x-ray may be normal.
Eventually, rales, rhonchi, and pleural friction rubs are noted, and
abnormal pulmonary function, with decreased lung capacity and increased
lung stiffness, is seen. Clinical parameters better predict outcome
than pulmonary function studies. Chest x-ray may reveal increased
interstitial markings, patchy reticulonodular infiltrates,
consolidation, or nodules indistinguishable from metastatic lesions,
which may cavitate. Biopsy findings are nonspecific. After the drug is
discontinued, reversal may take months, and fibrosis may be only
partially reversible and may be fatal. A number of investigational
approaches are being evaluated to prevent or reduce the severity of
this complication. [ref: 54,55,60-62]
Myelosuppression and immunosuppression are not prominent. Fevers
occur in 20% to 50% of patients, occasionally with hyperpyrexia.
Mucocutaneous toxicities are common, with mucositis; alopecia; and
hyperpigmentation, erythema, induration, hyperkeratosis, and peeling
that may progress to ulceration. The digits, hands, joints, and areas
of prior radiation or surgery are most affected. Acute arthritis may
occur.

L-Asparaginase

The growth of malignant and normal cells depends on the availability of
specific nutrients and cofactors required for protein synthesis. Some
nutrients can be synthesized within the cell, whereas others, such as
essential amino acids, require exogenous sources. L-asparagine is a
nonessential amino acid synthesized by the transamination of L-aspartic
acid by a reaction catalyzed by the enzyme L-asparagine synthetase. The
ability to synthesize asparagine is notably lacking in malignancies of
lymphoid origin. In 1953, Kidd [ref: 63] first reported that the growth
of transplantable lymphomas of rat and mouse was inhibited by guinea
pig serum, and subsequent experiments demonstrated that the responsible
factor was L-asparaginase. Subsequent purification from Escherichia
coli and Erwinia carotovora permitted production of large quantities of
the enzyme for clinical use. The purified bacterial enzyme has a
molecular weight of 133,000 to 141,000 daltons and is composed of four
subunits, each with one active site. The enzymes are specific for the
l-isomer. Asparaginase catalyzes the conversion of L-asparagine to
aspartic acid and ammonia. The enzyme does not enter cells, instead
degrading circulating asparagine to aspartic acid, which cannot be
converted to asparagine by the cancer cell. In contrast, most normal
cells can synthesize asparagine from aspartic acid by induction of
asparagine synthetase. This metabolic difference is not absolute, as
demonstrated by the toxicity profile of the agent. Resistance occurs
through increased expression of the asparagine synthetase gene, which
is transcriptionally silent in most tissues and leads to increased
enzyme synthesis in response to a decrease in intracellular L-
asparagine levels. [ref: 64] Resistance may also be mediated by the
formation of asparaginase antibodies that alter asparaginase
pharmacokinetics.

Clinical Pharmacology

L-asparaginase is administered either intravenously or intramuscularly.
The intramuscular route produces peak blood levels 50% lower than the
intravenous route, but the former may be less immunogenic and is more
commonly used. Three preparations of L-asparaginase are in clinical
use. The most widely used is derived from E coli, and an Erwinia
preparation is available for patients who develop hypersensitivity to
the E coli-derived agent. The usual doses are 6000 IU/m**2 three times
weekly for 3 to 4 weeks, or daily doses of 5000 to 20,000 IU/m**2 for
10 to 20 days. The optimal dose and schedule are unknown. Intermittent
schedules with less frequent administration are associated with reduced
efficacy and increased anaphylaxis. An E coli preparation modified by
the covalent attachment of polyethylene glycol (PEG) has a prolonged
half-life, thus permitting lower doses and less frequent
administration. [ref: 65] The approved dose of PEG-asparaginase is 2500
IU/m**2 every 14 days, either intravenously or intramuscularly.
L-asparaginase concentration in plasma is proportional to a total
dose up to 200,000 IU/m**2 and falls with a primary half-life of 14 to
22 hours after administration. Blood levels of the E coli enzyme are
detectable for 1 to 2 weeks after a single dose, and concentrations of
L-asparagine fall below 1 mmol within minutes of enzyme injection and
remain low for 7 to 10 days after completion of therapy. The half-life
is independent of the dose administered, disease status, renal or
hepatic function, age, or gender. The pharmacokinetics of asparaginase
depend on the preparation. [ref: 66-68] With E coli-derived enzyme, the
t(1/2) (1.14 to 1.35 days) administered by the intramuscular route is
the same irrespective of dose (2500 or 25,000 IU/mL) or with repeated
doses. Peak serum levels are reached in 24 to 48 hours and are no
longer detectable in serum by 10 to 14 days. Extremely low levels are
found in the urine at 24 hours, suggesting clearance of L-asparaginase
by mechanisms other than urinary excretion. Cerebrospinal fluid levels
disappear rapidly. The serum t(1/2) for Erwinia is 0.65 days, and
enzyme was no longer detectable by 7 days. This value is shorter than
the E coli preparation, although similar schedules are often used. The
serum t(1/2) of PEG-modified L-asparaginase as an initial dose was 5.73
days, which is significantly longer than after subsequent doses. [ref:
66]
Patients who experience a hypersensitivity reaction to E coli
asparaginase have a decreased t(1/2) subsequently with PEG
asparaginase. [ref: 66,69] Serum L-asparaginase activity is
undetectable in the week after an anaphylactoid reaction. And even a
"silent" anaphylactoid reaction to E coli may result in neutralizing
antibodies and reduced drug efficacy. [ref: 70]

Toxicities

L-asparaginase has no effect on bone marrow function. Hypersensitivity
is the most serious toxicity, and it occurs in fewer than 10% of
patients. It is manifested by urticaria, nausea, vomiting, and chills,
and less often by a serum sickness-like reaction or by anaphylaxis with
hypotension, laryngospasm, and cardiac arrest, which is fatal in fewer
than 1% of patients. Reactions generally occur during the second week
of treatment or later, and they mandate a change to another
preparation. The risk of hypersensitivity is greater when the drug is
used as a single agent than with concurrent immunosuppressive agents
(steroids, 6-mercaptopurine), at doses higher than 6000 IU/m**2/d
administered by the intravenous route and with repeated courses of
treatment. Neither skin testing nor antibody levels have been
sufficiently predictive. The PEG formulation is the least immunogenic
[ref: 71,72] and may be more cost-effective. [ref: 73] The development
of an allergic reaction does not appear to compromise the efficacy of
the agent. [ref: 74]
Decreased protein synthesis leads to reduced albumin and serum
lipoprotein concentrations. A reduction in vitamin K-dependent clotting
factors, a fall in fibrinogen levels, and decreased platelet
aggregation to collagen may lead to bleeding. Decreases in antithrombin
III, proteins C and S, and increased endogenous thrombin generation are
associated with venous thrombosis and embolism. [ref: 75-81] Other
toxic effects include confusion, aphasia, stupor, or coma in 25% to 33%
of patients[ref: 82,83]; hyperlipidemia [ref: 84,85]; and abnormal
liver enzymes with fatty metamorphosis. L-asparaginase is
contraindicated in patients with a history of pancreatitis because of
the risk of acute pancreatitis. [ref: 86]

Amifostine

Amifostine is a phosphorylated aminothiol prodrug analogue of
cysteamine. It was developed by the Walter Reed Army Medical Institute
(thus the military code name WR-2721) during the cold war as part of a
classified research project to identify an agent that would protect
military personnel from radiation in the event of nuclear war.
Amifostine was found to afford greater protection against radiation
than more than 4000 other compounds screened. Nevertheless, the army
terminated development of this compound in 1988 because of its poor
oral bioavailability and the prohibitive nausea, vomiting, diarrhea,
and abdominal cramps noted with the oral formulation.
When administered intravenously, the pharmacokinetics (PK) of
amifostine varies somewhat with dose. [ref: 87] The clearance from
plasma is rapid (distribution and elimination phases in humans of
t(1/2)alpha, less than 1 minute; t(1/2)beta, 8.8 minutes), with a
plasma half-life of 1 minute and almost all drug cleared by the plasma
within 10 minutes. Bioavailability from the subcutaneous route is high
but variable. [ref: 87,88]
Amifostine is dephosphorylated at the tissue level to its active
metabolite, the free thiol WR-1065, by membrane-bound alkaline
phosphatase. WR-1065 is rapidly taken up by cells and is thought to be
the major cytoprotective metabolite. WR-1065 protects normal cells by
acting as a free radical scavenger and by hydrogen donation to repair
damaged target molecules. [ref: 89,90]
Preclinical studies with amifostine suggested that the agent could
protect normal tissues from radiation and chemotherapy toxicity without
protecting tumors. [ref: 91-97] Phosphorylation of the aminothiol
contributes substantially to the selective uptake of WR-1065 by normal
kidneys, bone marrow, heart, and salivary glands compared with tumor
tissues. Several explanations have been postulated for this
preferential uptake, such as that concentrations of alkaline
phosphatase are higher in normal tissues compared with malignant
tissues. The hypovascular, hypoxic nature of tumors results in
anaerobic metabolism and a low interstitial pH, which are associated
with a low rate of prodrug activation by alkaline phosphatase.
Separate phase I trials of amifostine were conducted in conjunction
with radiotherapy or chemotherapy. A true maximum tolerated dose was
not identified in either setting, but the recommended dose ranges from
740 mg/m**2 to 910 mg/m**2. [ref: 98-101] No clear therapeutic
advantage to the higher doses has been determined. [ref: 100,102,103]
Drug-related toxicity appears to correlate with the duration of the
infusion. [ref: 104]

Chemotherapy-Related Nephrotoxicity

Amifostine has been evaluated for its ability to prevent chemotherapy-
related nephrotoxicity, especially that induced by cisplatin. [ref:
100-102,105] In the only phase III trial, Kemp et al. [ref: 106]
randomized 242 women with advanced ovarian cancer to six cycles of
chemotherapy, with or without amifostine, 910 mg/m**2, before each
cycle. The severity of renal toxicity was reported to be lower in the
group receiving amifostine. Fewer patients discontinued therapy on the
amifostine arm because of toxicity. The response rates and survival
durations were comparable between the two arms. However, the doses of
cisplatin used in this study are higher than the dose currently
recommended, and this regimen is less commonly used than other less
nephrotoxic programs.

Neurologic Toxicities and Ototoxicity

Several small phase II studies and one phase III trial suggest that
amifostine may offer modest protection against the neurologic
toxicities of cisplatin, but with no effect on ototoxicity. [ref:
101,105,106]

Neutropenia and Thrombocytopenia

Various phase I, II, and III trials suggest a myeloprotective effect
from amifostine. Glover et al. [ref: 103] conducted a phase II trial of
amifostine in combination with cyclophosphamide with 21 patients used
as their own controls; 90% had an improved white blood cell count with
the second course of cyclophosphamide compared with the first course.
Whether these findings are clinically meaningful is questionable. [ref:
103,106,107] In a study conducted by the Cancer and Leukemia Group B,
[ref: 108] patients with solid tumors were treated with high-dose
cyclophosphamide with amifostine alone or with amifostine and
granulocyte-macrophage colony-stimulating factor. No additional
protection was noted with the combination.
Preliminary phase I data suggest less thrombocytopenia in patients
treated with carboplatin and amifostine. [ref: 109] However, the
aggregate data from subsequent studies provide less support for
clinically meaningful benefit. [ref: 108,110-113]

Additional Observations

Limited data suggest that amifostine may modulate the cardiotoxicity of
doxorubicin and the pulmonary toxicity of bleomycin. [ref: 54,55,114]

Radioprotection

Amifostine has been evaluated in combination with radiation therapy or
combined modality treatment for patients with head and neck and lung
cancers. [ref: 111,115-124] The suggestion has been made of a reduction
in esophagitis in lung cancer patients and less xerostomia and loss of
taste with amifostine, but with no clear impact on mucositis or
salivary gland function. [ref: 117-119] There is no clear
radioprotective effect in patients with rectal cancer. [ref: 98,125]

Toxicities

The major toxicities associated with amifostine include nausea and
vomiting, hypotension, hypocalcemia, and allergic reactions. The onset
of nausea and vomiting is generally within 15 to 30 minutes of the
start of the infusion, and they resolve spontaneously. Pretreatment
with dexamethasone and a 5-hydroxytryptamine receptor antagonist is
recommended.
Hypotension is a potentially serious side effect. It is generally
systolic, lasting 5 to 15 minutes, without central nervous system,
renal, or cardiovascular consequences. Administration issues that
influence the frequency and severity of hypotension include patient
hydration, infusion duration, position of patient, and antiemetic
pretreatment. Patients should not be receiving agents that potentiate
the potential for hypotension, and the drug should not be administered
to patients who cannot be without antihypertensive medications for at
least 24 hours. Dehydrated patients should not receive the drug until
the problem has been corrected. Patients should be hydrated before
administration of amifostine. Patients should remain supine or
reclining during amifostine therapy.
Hypocalcemia is clinically significant in approximately 1% of
patients and can be managed with oral calcium carbonate and vitamin D.
The drug has been used successfully to treat hypercalcemia. [ref: 126]
Allergic reactions occur in fewer than 1% of patients and are
successfully treated with diphenhydramine.

Drug Administration

Amifostine should be administered over 15 minutes, 5 to 30 minutes
before cytotoxic chemotherapy. The patient should be well hydrated and
in a reclining position, with frequent blood pressure monitoring. The
recommended dose with radiation therapy is 200 mg/m**2/d, as a slow
intravenous push over 3 minutes, 15 to 30 minutes before each radiation
fraction. Bolus schedules have been studied as well. [ref: 127]

Myelodysplastic Syndromes

Amifostine stimulates hematopoiesis in animal models, and in in vitro
studies it stimulates the formation of hematopoietic progenitors from
myelodysplastic syndrome bone marrow. [ref: 128] In a phase I/II study,
[ref: 129,130] the drug was administered at doses of 100, 200, or 400
mg/m**2 three times per week, or 740 mg/m**2 weekly for 3 weeks.
Hematologic improvement was observed in 83% of patients with the
thrice-weekly schedule, including either an increase in neutrophils or
a reduction in red blood cell transfusion requirements. More than 40%
of patients had a rise in their platelet counts. Acceleration to acute
myeloid leukemia was noted in several patients with RAEB-T (refractory
anemia with excess of blasts in transformation). In a subsequent
multicenter trial, [ref: 131] there was single or multilineage
improvement in 35%. A poor response rate was reported using a
continuous schedule of eight uninterrupted thrice-weekly doses of 300
to 450 mg/m**2. [ref: 132] The role of this agent in myelodysplastic
syndrome is being elucidated.

Recommendations for the Use of Amifostine

Based on a careful review of the data, the American Society of Clinical
Oncology made the following recommendations regarding the use of
amifostine[ref: 133]:
- It may be considered for the reduction of nephrotoxicity in
patients receiving cisplatin-based chemotherapy.
- Although it may be considered for the reduction of neutropenia in
patients receiving alkylating agents, chemotherapy dose reduction or
growth factor use should be considered as an alternative to the use of
amifostine.
- Present data are insufficient to recommend the use of amifostine
for protection against thrombocytopenia or the routine use of
amifostine to prevent cisplatin-associated neurotoxicity or
ototoxicity. Similarly, the data were felt to be insufficient to
support the use of amifostine for the prevention of paclitaxel-
associated neurotoxicity.
- The use of amifostine may be considered to decrease the incidence
of acute and late xerostomia in certain patients undergoing
fractionated radiation therapy in the head and neck region, although
the present data are insufficient to recommend the use of amifostine to
prevent radiation therapy-associated mucositis.