The Role of Amifostine as a Radioprotector

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(Drug information on 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(Drug information on 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(Drug information on 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(Drug information on 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]