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The Role of Amifostine as a Radioprotector

The Role of Amifostine as a Radioprotector

ABSTRACT: Effective radiotherapy for patients with cancer should include maximal tumor cell killing with minimal injury to normal tissue. Radiation doses that can be delivered, without causing severe damage to surrounding normal tissues, can be insufficient to eradicate a tumor. Agents have been developed to protect normal tissue from the toxicities of radiation. The aminothiol amifostine (Ethyol) is the subject of extensive research as a protector. Several studies have demonstrated that amifostine protects normal tissues from both acute and late radiation damage without protecting the tumor. This article reviews the physicochemical basis of radiation therapy on biologic tissues and the mechanisms responsible for the protective effects of amifostine. The increasing body of biochemical, preclinical, and clinical data can justify the use of protectors such as amifostine with radiotherapy to provide improved therapeutic efficacy and quality of life for the patient. This article will review the current understanding of the nature of toxicity resulting from radiation therapy and the benefits that can be derived from using protection to increase the tolerance of normal tissue to radiation damage. [ONCOLOGY 15:1349-1360, 2001.]

The goal of radiation therapy is to
eradicate tumors or to reduce their size to make them easier to remove
surgically. Advances in radiation oncology have sought to increase therapeutic
efficacy while preserving normal tissues. Equipment capable of generating
high-energy photons and high-energy electron beams have increased the
penetration of radiation, facilitating access to deep-seated tumors and reducing
scattering to adjacent normal tissues.

Variation of radiation schedules, including the simultaneous
decrease of the dose while increasing the number of daily fractions (hyperfractionation),
has improved response rates in some settings.[1-3] Three-dimensional conformal
radiotherapy (3D-CRT)[4] and stereotactic radiotherapy[5] are both aimed at
reducing damage to surrounding normal tissue while concentrating the radiation
to the tumor.

Although these advances have reduced the possibility of
damage to normal tissue, further improvements are still needed. Certain cancers
with proximal tumor spread (such as Hodgkin’s disease and lung cancer) require
large-field radiation therapy, which increases the potential for injury to
normal tissue.

Protecting the body from the toxicities of radiation has been
a major concern since the effects of radiation were graphically demonstrated at
the end of World War II.

Radiation-Induced Cellular Damage
and Toxicity

Since rapidly dividing tissues are more vulnerable to lethal
DNA injury,[6] manifestations of radiation toxicity include oral and
gastrointestinal mucositis and hematologic toxicity. When radiation is
administered with chemotherapy, multiple toxicities may result. In addition to
acute toxicity, radiation injuries may become permanent. Toxicity is often
confined to the site of radiation.

Because a linear relationship exists between radiation dose
and permanent cell damage, more intensive radiation is more likely to be
effective against cancer cells. Consequently, to maximize the therapeutic
benefit to the patient and minimize the adverse effects on normal tissues, a
delicate balance must be established between radiation dose and target volume.

The benefits of protecting normal tissues from the adverse
effects of radiation therapy include the prevention of debilitating toxicities,
maintenance of an effective immune system, improved DNA repair, and reduction of
the mutagenic potential of irradiation. Protection should decrease the
occurrence of toxicities, which should increase a patient’s quality of life.

While secondary tumors may take many years to develop and the
incidence resulting from radiation may be low, the increased risk of secondary
neoplasms is a concern for patients whose cancer has a good chance of long-term
remission (as in Hodgkin’s disease).[7]

Clinical Trials

Developed by the Army as 1 of 4,400 compounds tested,
amifostine (Ethyol) remains the best drug to date to be tested as a
radioprotector.[8,9] It is unlikely that further drug development will occur.
Studies began at the National Cancer Institute in 1973, and the drug was
eventually licensed to US Biosciences—now Medimmune Oncology—with sales
agreements with Alza and Schering.

A number of thio-organic compounds have been developed as
adjuncts to radiotherapy. Among these, amifostine is currently approved as a
protector against cisplatin (Platinol)-induced toxicity in the United States and
cisplatin- and cyclophosphamide (Cytoxan, Neosar)-induced toxicities in Europe.
It is also used for radioprotection against xerostomia.

In the United States, phase I trials of amifostine
(originally known as WR-2721) were performed by the Radiation Therapy Oncology
Group (RTOG).[10,11] The maximum tolerated single dose of amifostine was
established with single-dose and fractionated radiation therapy.

In the single-dose toxicity study of amifostine, 201 patients
were entered. Drug doses were escalated between 25 and 1,330 mg/m² according to
a modified Fibonacci schedule. Toxic reactions in the single-dose study included
hypotension, emesis, somnolence, sneezing, metallic taste, and hypocalcemia. The
two major toxicities were emesis and hypotension, and their incidence increased
with dose. It was concluded that the dose-limiting toxicity for a single dose of
amifostine is emesis and that 740 mg/m² delivered in 15 minutes represents the
maximum tolerated dose. No clinical evidence of tumor protection was seen in any
of these patients, and no drug-related deaths occurred.

Eighty-four patients were entered into a multiple-dose
trial.[10] Doses were escalated from 100 mg/m² once a week to 450 mg/m² four
times a week for 5 weeks. It was concluded that 340 mg/m² four times per week
for 5 weeks before radiation therapy was the maximum tolerated dose. This dose
in humans corresponds to a dose level in mice at which effective radioprotection
was observed. No long-term chemical, hematologic, or enzymatic changes were
observed in any patients treated with amifostine, and there were no drug-related
deaths.

In another more recent trial, twice-daily amifostine was
poorly tolerated when used with accelerated radiation.[12]

Phase I/II Studies

In 1980, Tanaka[13,14] reported a phase II clinical study of
amifostine with radiotherapy, which demonstrated that amifostine protected
nearly 60% of patients receiving radiation therapy for cancer of the head and
neck, lung, breast, and uterus from increased toxicity.

Subsequently, amifostine was used with radiation therapy in
various phase II trials (Table 1).[15-24] A direct comparison of these results
is difficult because of differences in the drug and radiation regimens that were
used. However, these studies show that amifostine can provide protection against
radiation therapy toxicities.

Head And Neck Cancers

Radiotherapy of the head and neck commonly results in
dose-limiting mucositis. Radiation to this region can also cause significant
acute and chronic dysfunction of the salivary gland (xerostomia). Collectively,
these effects can lead to severe secondary complications, including pain and
difficulty in speaking and swallowing, decreased appetite, and weight loss.
Clinical studies were conducted to determine the usefulness of amifostine as an
adjunct to radiotherapy of the head and neck.

Büntzel[17] studied the protective effect of amifostine
against concurrent chemoradiotherapy in head and neck cancer. This was a small
randomized study of 39 stage III/IV head and neck cancer patients. Amifostine
was given at 500 mg IV, but only on days when carboplatin (Paraplatin) was
administered along with radiation. Patients receiving amifostine had
significantly reduced mucositis and xerostomia in comparision with patients
receiving radiochemotherapy alone. The patients treated with amifostine also had
significantly less thrombocytopenia and leukocytopenia. There was no reduction
in disease control when the two arms were compared. At 12 months after
treatment, there was no evidence of disease in 79% of the amifostine-pretreated
group vs 64% of the control group.

Busch et al[18] demonstrated the ability to deliver salvage
radiation with amifostine pretreatment in patients with recurrent head and neck
cancer. Salvage radiation is often precluded because of the severity of
radiation-induced toxicity.

Thyroid cancer can be effectively treated with high-dose
iodine-131, but treatment often results in a reduction in salivary gland
function. In a recent prospective, double-blind, placebo-controlled trial,[19]
patients receiving amifostine (500 mg/m²) before radioiodine therapy exhibited
no significant decrease in efficacy (P = .878) and no xerostomia, whereas
control patients experienced a significant reduction in parotid (37%) and
submandibular (31%) function, as measured by pertechnetate scan uptake (P =
.01). Grade 1 xerostomia developed in 33% of patients in the iodine-131 group
only.

Tumors of the Cervix and Pelvis

Data from a New York Gynecologic Oncology Group study of
patients with cervical cancer who received amifostine (340 to 910 mg/m²) before
cisplatin and whole-pelvic irradiation suggest that, relative to historical
controls, patients treated with amifostine had less radiation toxicity to the
pelvic mucosa—in particular, late toxicities such as rectovaginal fistula and
proctitis.[25]

Lymphoid Malignancies and Bone Marrow Metastases

Investigation of amifostine in hematologic malignancies is
important because lymphoid malignancies and cancers that metastasize to the bone
marrow usually require irradiation to large areas of the body. A phase I
dose-ranging study in patients with indolent non-Hodgkin’s lymphoma or chronic
lymphocytic leukemia tested the MTD of amifostine, 910 mg/m² twice weekly, in
conjunction with total body irradiation, for at least five treatments.[26] The
investigators noted that the induction of adverse side effects—primarily
malaise and less often hypotension and nausea and vomiting—appears to be
related to the cumulative dose of amifostine.[27]

The ability of amifostine to reduce bone marrow toxicity from
radiation was demonstrated in a study of patients undergoing hemibody
irradiation at a dose of 60 or 70 Gy. Patients pretreated with amifostine had no
grade 4 bone marrow toxicity, compared to 10% in patients receiving hemibody
irradiation alone (Table 1).[24]

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