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Amifostine Use in Radiation Therapy Associated Complications

1. Xerostomia 1999-2002 Recommendation:
ASCO recommends that amifostine may be considered to decrease the incidence of acute & late xerostomia in pts undergoing fractionated radiation therapy in the head & neck region.

2. Mucositis 1999-2002 Recommendation:
Insufficient data to recommend amifostine to prevent mucositis associated with RT.

Dose and Administration of Amifostine With Radiation Therapy
1999-2002 Recommendations from ASCO:
The recommended amifostine dose is 200 mg/m2/d, slow IV push over 3 minutes, 15 - 30 minutes before each RT fraction. Administration requires close patient monitoring. Noe that side effects are fewer at this lower dose. Many patients require antiemetics. Blood pressure should be measured just before & immediately after the 3-minute amifostine infusion. The hypotension associated with amifostine at this dose is less frequent but still requires close monitoring.

2002 Update: Ongoing trials are evaluating subcutaneous administration of amifostine when given daily with RT. In one study, amifostine-related local toxicity included only mild pain at the site of injection & local erythema. Systemic side effects included nausea, vomiting, & cumulative severe asthenia. No hypotension was reported. No data from randomized clinical trials available that the subcutaneous route is as effective as the IV route of administration in protecting against xerostomia.

Journal of Clinical Oncology, Vol 20, Issue 12 (June), 2002: 2895-2903
------------------------------------------------------------------------

ASCO SPECIAL ARTICLE

2002 Update of Recommendations for the Use of Chemotherapy and Radiotherapy Protectants: Clinical Practice Guidelines of the American Society of Clinical Oncology
THE AMERICAN SOCIETY of Clinical Oncology (ASCO) published evidence-based clinical guidelines for the use of chemotherapy and radiotherapy protectants in 1999.1 ASCO guidelines are updated periodically by a subset of the original expert panel. For the 2002 guideline update, the expert panel co-chairs reviewed the data published since 1998. Computerized literature searches of MEDLINE and CancerLIT were performed. The searches of the English-language literature from 1997 to 2001 included each of the protectants (mesna, dexrazoxane, and amifostine) evaluated in the original guideline. The term "mesna" was combined with "cyclophosphamide," "oral administration," and "ifosfamide"; the term "dexrazoxane" was combined with "breast cancer" and with "cardiac"; and the term "amifostine" was combined with "nephrotoxicity," "neutropenia," "thrombocytopenia," "radiation therapy," "paclitaxel-associated neurotoxicity," and "chemotherapy." The search was further limited to human studies and review articles or randomized controlled trials.
GUIDELINES FOR THE USE OF AMIFOSTINE TOP
INTRODUCTION
GUIDELINES FOR THE USE...
GUIDELINES FOR THE USE...
GUIDELINES FOR THE USE...
APPENDIX Conflict of Interest...
REFERENCES
 
Amifostine Use in Chemotherapy-Associated Complications
1. Nephrotoxicity 1999 Recommendation: Amifostine may be considered for the prevention of nephrotoxicity in patients receiving cisplatin-based chemotherapy.

2002 Update: There have been no new randomized studies addressing the efficacy of amifostine for preventing nephrotoxicity in patients receiving cisplatin-based chemotherapy. The FDA has approved amifostine to reduce the cumulative renal toxicity associated with repeated administration of cisplatin in patients with advanced ovarian cancer or nonsmall-cell lung cancer. Results from these studies, which were reviewed in the original guideline,19,20 do not suggest that the effectiveness of cisplatin-based chemotherapy is altered by amifostine. The FDA indication further states that there are only limited data on the effects of amifostine on the efficacy of chemotherapy in other settings and that therefore amifostine should not be administered to patients in settings where chemotherapy can produce a significant survival advantage or cure, except in the context of a clinical trial.

2002 Recommendation: No change.

2. Neutropenia 1999 Recommendation: The panel recommends that amifostine be considered for the reduction of neutropenia-associated events in patients receiving alkylating-agent chemotherapy. However, in the absence of clinical data supporting maintenance of the chemotherapy dose-intensity, physicians should consider chemotherapy dose reduction as an alternative to the use of amifostine.

2002 Recommendation: No change.

3. Thrombocytopenia 1999 Recommendation: Present data are insufficient to recommend the use of amifostine for protection against thrombocytopenia in patients receiving alkylating-agent chemotherapy or carboplatin.

2002 Recommendation: No change.

4. Neurotoxicity and Ototoxicity 1999 Recommendation: Present data are insufficient to support the routine use of amifostine for the prevention of cisplatin-associated neurotoxicity or ototoxicity.

2002 Recommendation: No change.

5. Paclitaxel Associated Neurotoxicity 1999 Recommendation: Present data are insufficient to support the use of amifostine for the prevention of paclitaxel-associated neurotoxicity.

2002 Update: Since the publication of the 1999 guideline, a randomized phase II study of high-dose paclitaxel with amifostine has been published.20 In this study, 40 patients with metastatic breast cancer were randomized to receive paclitaxel or paclitaxel preceded by amifostine (910 mg/m2). The dose of paclitaxel was 250 mg/m2, administered over 3 hours. The amifostine was administered over 15 minutes just before the paclitaxel infusion. Patients completed questionnaires for neurologic symptoms and had standardized neurologic examinations, including objective assessments of power and vibration sense. Overall, there was no difference between the treatment arms on any of the measures of neurotoxicity. However, there were some nonsignificant trends in the frequency of grade 2 and 3 neurosensory toxicity in favor of the amifostine arm. Pharmacokinetic studies were also performed on a subset of patients. Paclitaxel plasma levels were determined and found to be comparable in the presence or absence of amifostine. Thus, there was no evidence that amifostine altered the clearance of paclitaxel. The results from this randomized phase II study do not show evidence of amifostine protection against paclitaxel neurotoxicity. However, these results must be interpreted cautiously as the study was a randomized phase II study and may have been underpowered to detect a clinical difference. A larger, phase III clinical trial would be required to more definitively assess the role of amifostine when given with paclitaxel.

2002 Recommendation: There are no data to support the use of amifostine for prevention of paclitaxel-associated neurotoxicity.

Dose and Administration of Amifostine With Chemotherapy
1999 Recommendation: In adults, the suggested dose of amifostine with chemotherapy is 910 mg/m2. Amifostine is administered intravenously, over 15 minutes, 30 minutes before chemotherapy. Administration of amifostine requires close patient monitoring, and toxicity is clearly dose related. All patients should be treated with antiemetics before the administration of amifostine, and pretreatment with intravenous fluids should also be considered. Blood pressures are taken every 3 to 5 minutes during the 15-minute infusion. Amifostine is discontinued if blood pressure declines significantly or the patient becomes symptomatic. The hypotension associated with amifostine usually occurs at the end of the infusion and is reversed with discontinuation of the amifostine, administration of saline, and placing the patient in the Trendelenburg position. There are insufficient data to recommend redosing of amifostine after chemotherapy.

2002 Recommendation: No change.

Amifostine Use in Radiation TherapyAssociated Complications
1. Xerostomia 1999 Recommendation: The panel recommends that amifostine may be considered to decrease the incidence of acute and late xerostomia in patients undergoing fractionated radiation therapy in the head and neck region.

2002 Update: The most common and clinically significant toxicities arising from head-neck irradiation are acute mucositis and acute and chronic xerostomia. Small clinical trials have suggested that amifostine protects against radiation-induced toxicity.21 Since the publication of the 1999 guideline, the final results of a phase III randomized trial of amifostine as a radioprotector in head and neck cancer were published. In that study, 315 patients with previously untreated squamous cell cancer of the head and neck were randomized to radiation alone versus radiation plus amifostine 200 mg/m2 over 15 to 30 minutes before each radiation therapy treatment. This study demonstrated that amifostine reduced acute and chronic xerostomia while preserving antitumor efficacy.22 Amifostine reduced the overall incidence of grade 2 or higher acute xerostomia from 78% to 51% (P < .0001). The radiation dose associated with this side effect in 50% of all patients was higher in those patients receiving amifostine compared with those who did not (60 Gy v 42Gy, respectively, P = .001). Chronic xerostomia (symptoms 1 year after completion of treatment) occurred in 34% of patients who received amifostine versus 57% in those who did not (P = .002). Patients who received amifostine also produced more saliva at 1 year compared with those who did not receive treatment. Amifostine was well tolerated. Nausea, vomiting, and allergic reactions were the most common side effects. Hypotension, usually mild and of short duration, was associated with less than 1% of all amifostine dosages. Complications related to venous catheters occurred in 5% of patients treated with amifostine. There was no evidence that amifostine interfered with the antitumor effects of radiation therapy as measured by local/regional control and overall survival.

Further analysis of this study included a patient benefit questionnaire, which assessed areas such as difficulty speaking and eating, sleep problems, and use of oral comfort aids or fluids. Results of this study showed that amifostine-treated patients consistently reported better patient benefit questionnaire scores, which was indicative of improved oral toxicityrelated outcomes and improved clinical benefit.23

These data are further supported by a small, double-blind, placebo-controlled study in patients with thyroid cancer undergoing treatment with high-dose radioiodine treatment. Fifty patients were randomly assigned to saline or to amifostine 500 mg/m2 over 15 minutes before radioiodine treatment. Eleven of the 25 control patients developed grade 1 or 2 xerostomia, while none of the patients treated with amifostine developed xerostomia.24 Finally, a small randomized study demonstrated that amifostine protected against worsening dental health in patients receiving radiation therapy for head and neck cancer.25

2002 Recommendation: No change.

2. Mucositis 1999 Recommendation: Present data are insufficient to recommend amifostine to prevent mucositis associated with radiation therapy.

2002 Update: As presented above, since the publication of the 1999 guidelines, the final results of a phase III randomized trial of amifostine as a radioprotector in head and neck cancer were published. Three hundred fifteen patients with previously untreated squamous cell cancer of the head and neck cancer were randomized to radiation alone versus radiation plus amifostine 200 mg/m2 over 15 to 30 minutes before each radiation therapy treatment. Although this study demonstrated that amifostine reduced acute and chronic xerostomia, amifostine did not reduce the incidence of mucositis. Grade 3 or higher mucositis occurred in 35% of the amifostine group and in 39% of the radiotherapy-alone patients (P = .48). The median duration of mucositis was also similar in the two groups of patients (amifostine group, 41 days v radiotherapy-alone group, 38 days; P = .685).22

In another radioprotector study, the role of amifostine administered subcutaneously was evaluated in a randomized phase II study. In this study, 140 patients with locally advanced cancer were categorized into three separate regions: head and neck, thoracic, and pelvic localization.26 Randomizations were performed separately for these three different tumor locations. The dose of amifostine was 500 mg, diluted in 2.5 mL of normal saline and injected subcutaneously, daily, 20 minutes before each radiotherapy fraction. Overall, the results from this study showed a reduced severity of symptoms related to mucositis in those patients treated with amifostine. In the patients treated for gynecologic and rectal tumors, less severe skin radiation toxicity was seen in the perineal/vulvar area in patients treated with amifostine. A phase III study will be required to confirm these preliminary results.

Amifostine has also been evaluated in patients receiving accelerated radiation therapy. Clinical trials of accelerated irradiation suggest improvement of tumor control rates when compared with conventional radiotherapy in patients with head and neck cancer.27 Accelerated radiation is associated with an increased risk of acute reactions. In a small, randomized trial of 26 patents with inoperable stage IV head and neck cancer, patients were randomized to receive or not amifostine 150 mg/m2 IV 15 to 30 minutes before each radiation therapy session.28 Radiation therapy (64 Gy) was delivered over 22 to 23 days. Results from this pilot study suggest that amifostine was able to reduce the severity and duration of mucositis as measured by treatment interruptions, duration of grade 3 mucositis (25.1 days v 49.2 days; P = .03), and need for a feeding tube. Ongoing studies will further define the role of amifostine in protecting against radiation-induced mucositis.

2002 Recommendation: No change.

Dose and Administration of Amifostine With Radiation Therapy
1999 Recommendation: When given with radiation therapy, the recommended amifostine dose is 200 mg/m2/d, given as a slow IV push over 3 minutes, 15 to 30 minutes before each fraction of radiation therapy. Administration of amifostine requires close patient monitoring, but side effects are fewer at this lower dose. Many patients require antiemetics. Blood pressure should be measured just before and immediately after the 3-minute amifostine infusion. The hypotension associated with amifostine at this dose is less frequent but still requires close monitoring.

2002 Update: There are no data from randomized clinical trials that test different doses of amifostine in conjunction with radiation therapy. Therefore, the recommendation for dose and schedule of amifostine with radiation therapy has not changed. Ongoing trials are evaluating subcutaneous administration of amifostine when given daily with radiation therapy. In one study, amifostine-related local toxicity included only mild pain at the site of injection and local erythema. Systemic side effects included nausea, vomiting, and cumulative severe asthenia. No hypotension was reported.26 There are no data from randomized clinical trials that show that the subcutaneous route is as effective as the IV route of administration in protecting against xerostomia.

2002 Recommendation: No change.