Amifostine

DATABASES USED: MEDLINE (May 2002–May 2005), selected studies related to amifostine

KEYWORDS: stomatitis, mucous membrane, mucositis (text in titles and abstracts)

INCLUSION CRITERIA: Limited to \"neoplasm\" and English language

FINAL NUMBER STUDIES INCLUDED = 29 trials included, 6 covered in detail; pilot studies and randomized, controlled studies included

SAMPLE RANGE ACROSS STUDIES: Sample sizes range from small to more than 200

KEY SAMPLE CHARACTERISTICS: Patients with head and neck cancer receiving radiation alone; patients with cancers of various origin receiving combination chemoradiation or radiation alone; patients receiving intensity-modulated radiation therapy; and studies examining routes of administration in patients with head and neck cancer, patients with prostate cancer, and patients receiving epirubicin

The study did not provide sufficient evidence for recommendations related to amifostine and prevention or management of oral mucositis. The authors recommended maintaining the original guideline from the Multinational Association of Supportive Care in Cancer—chemoradiation for non-small cell lung cancer for prevention of esophagitis (level of evidence III, grade of recommendation C). Several small studies demonstrated prevention of proctitis in patients with only rectal carcinoma. No effect was shown for other pelvic cancers. Therefore, the authors suggested that the guideline be revised to include the recommendation of amifostine at least 340 mg/m² IV daily prior to radiation (level of evidence III, grade of recommendation B) for rectal carcinoma to prevent proctitis. For patients with hematologic disorders, no significant data could reinforce any recommendations. Possible future uses and routes of amifostine also were discussed.

STUDY PURPOSE: To review available literature from 1966 to December 31, 2010 to define clinical practice guidelines for the use of amifostine for prevention and treatment of oral mucositis in patients with cancer

TYPE OF STUDY: Systematic review

DATABASES USED: MEDLINE

KEYWORDS: Extensive list provided (anti-inflammatory agents) including amifostine, antitumor necrosis factor (TNF), non-steroidal anti-inflammatory drugs, TNF inhibitor, etc.

INCLUSION CRITERIA: Detailed information is provided in a different section of the journal. Studies relevant to the management of radiation and/or chemotherapy-induced oral mucositis using anti-inflammatory interventions including amifostine

EXCLUSION CRITERIA: Articles that did not report on intervention and mucositis outcomes, animal or in vitro studies, non-English articles, methodologic quality, and anti-inflammatory agents other than amifostine

TOTAL REFERENCES RETRIEVED: 908

EVALUATION METHOD AND COMMENTS ON LITERATURE USED: Only articles that investigated amifostine specifically were selected. Levels of evidence were based on the Somerfield criteria, and study methodology was evaluated on the Hadorn criteria. These were integrated into guideline categories—recommendation, suggestion, or no guideline possible.

• FINAL NUMBER STUDIES INCLUDED = 30
• SAMPLE RANGE ACROSS STUDIES, TOTAL PATIENTS INCLUDED IN REVIEW: Not indicated
• KEY SAMPLE CHARACTERISTICS: Head and neck, high-dose chemotherapy, chemotherapy and radiation

PHASE OF CARE: Active antitumor treatment

No guideline, suggestion, or recommendation for mucositis prevention with amifostine was possible in any of the following groupings.

• Head and neck radiotherapy
• Head and neck chemotherapy/radiation
• High-dose chemotherapy
• Standard-dose chemotherapy
• Radiotherapy alone
• Chemotherapy/radiation prevention

Conflicting results, insufficient data, and major Hadorn flaws did not allow any guideline related to the use of amifostine for oral mucositis prevention. New well-designed trials are necessary that include timing of amifostine infusion prior to radiotherapy, consistent dose of amifostine, and cancer therapy intensity and modality.

Too many studies may have been eliminated up front.

Because no guidelines are recommended by this review, nurses who continue to administer amifostine for mucositis prevention carefully should document the results and look for ways to participate in well-designed trials. Nurses may consider advocating against the use of amifostine outside of research until guidelines can be established for its use.

Patients in the study group received 300 mg/m² amifostine 15–30 minutes before radiation therapy (RT) on days 1–5 of each week. Patients in both the study group and the control group received 90 mg/m² carboplatin once per week before RT. Treating physicians and patients reported data.

• The study enrolled 50 patients. Of these, 45 were assessable (22 in the study group and 23 in the control group).
• More men than women participated.
• The mean age was 59 years with a  range of 45–74 years.

The study was conducted between January 1997 and January 1998.

The Radiation Therapy Oncology Group/ European Organization for Research and Treatment of Cancer (RTOG/EORTC) 0–4 grading system was used.

• Mucositis increased from baseline to grade 2 more rapidly in the control group by week 3.
• In the control group, 23 patients (100%) experienced grade 2 mucositis versus only two patients (91%) in the study group (p < 0.0001).
• Most patients receiving amifostine (77.2%) experienced mild mucositis (grade 2) versus only 21% in the control group (p = 0.0001).
• During week 5, 52% of patients in the control group had grade 4 mucositis versus 4.5% of patients in the study group (p = 0.0006).
• The majority of patients in the control group (95.7%) experienced moderate to severe mucositis versus 63.6% of patients in the study group (p = 0.0098).
• Incidence of side effects was low with nausea and vomiting (4.5%) and hypotension (13.6%) most common.

• The sample size was small, and the study was not blineded.
• Limited mucositis data were presented.

To evaluate the efficacy and safety of IV amifostine during radiochemotherapy for head-and-neck cancer

Patients in the study group received 300 mg/m² IV amifostine on the days in which they received carboplatin and radiation therapy (RT). On the days in which they received only RT, they were given 200 mg/m² IV amifostine.

• The study reported on 132 patients (67 in the amifostine group and 65 in the placebo group).
• The median age of patients in the amifostine group was 57 years and the median age of patients in the placebo group was 58 years. Patients' ages ranged from 23–78 years.
• This was a randomized, double-blind, placebo-controlled, phase III, multicenter study.
• Patients had been diagnosed with stage III or IV head and neck cancer and were receiving RT and 70 mg/m² carboplatin.

The study was conducted between October 1996 and October 1999.

• Radiation Therapy Oncology Group (RTOG) scoring was used.
• The Acute/Late Radiation Morbidity Scoring Criteria were used.

• Effectiveness not established; no statistical evidence was found to indicate that mucositis was improved with the use of amifostine versus placebo.
• In the amifostine group, 39% of patients experienced grade 2 or higher xerostomia; in the placebo group, 35% of patients experienced grade 2 or higher xerostomia (p = 0.715).
• In the amifostine group, 39% of patients experienced grade 3 or higher xerostomia; in the placebo group, 22% of patients experienced grade 3 or higher xerostomia (p = 0.055).
• In the amifostine group, 47 patients completed the study; in the placebo group, 55 patients completed the study.
• The most common reactions were nausea/vomiting, hypotension, allergic reaction, and rash.
• In the amifostine group, 30% of patients discontinued treatment versus 11% in the placebo group.

The intervention was not found to be effective in the management of mucositis toxicity.

This was the first randomized and placebo-controlled study of amifostine in the head and neck cancer population.

Patients were given 1,000 mg/day IV amifostine (740 mg/m²) once a day or divided (depending on frequency of chemotherapy or total body irradiation [TBI]), rounded to nearest 500 mg, and given over 15 minutes prior to chemotherapy or TBI. 

• The study reported on 60 patients (30 in the amifostine group and 30 in the control group).
• Median age was 28 years in the amifostine group and 30 years in the control group. Ages ranged from 15–47 years old.
• Patients were receiving allogeneic hematopoietic stem cell transplant (HSCT).
• Treatment regimens were busulfan and cyclophosphamide, cyclophosphamide and TBI, or etoposide.

This was a single-institution, randomized, open-label trial conducted between August 1998 and October 2003.

The World Health Organization (WHO) Mucositis grading scale was used daily during the study, followed by the Common Toxicity Criteria in Cancer Therapy Evaluation Program (CTEP).

• No significant differences were found between the groups in grades of mucositis; however, duration of all grades of mucositis was significantly reduced in the amifostine group. Patients in the amifostine group experienced a shorter overall duration (16 days versus 21 days, p < 0.02). They also had a shorter duration of grade 3 or 4 mucositis (0 days versus 5 days), but this difference was not significant (p = 0.3).
• Patients who received amifostine had lower incidence of grade 3 or 4 mucositis (41% versus 63%), but this difference was not significant (p = 0.44).
• Side effects included nausea and vomiting, hypotension, and hypocalcemia.

• The exact dosing of amifostine was difficult to determine when divided doses were given.
• Only used sibling allogeneic transplants.

• Patients received 910 mg/m² IV amifostine as a 15-minute infusion prior to 200 mg/m² melphalan.
• Ten consecutive patients who were treated within the same protocol without amifostine were used as controls.
• Patients received granulocyte colony-stimulating factor (G-CSF) from day +4 to neutrophil recovery.

• The study reported on a sample of 20 patients.
• All patients were receiving 200 mg/m² high-dose melphalan and autologous stem-cell transplant (ASCT).
• Patients were given cytoxan, mesna and G-CSF for mobilization.

The study was conducted between November 1998 and February 2000.

This was a pilot, feasibility study.

The National Cancer Institute (NCI) Common Toxicity Criteria for Oral Mucositis was used to assess oral mucositis daily.

Most of the patients (9 out of 10) received the full dose of amifostine. One patient received only 780 mg/m² because of recurrent hypotension. Significant nausea, as well as hypotension and vomiting, occurred.

Amifostine did not show a benefit for gastrointestinal toxicity or mucositis of more than grade 2.

• This was a feasibility study.
• The sample size was small.

Patients receiving carboplatin (area under the curve [AUC] 5 mg per minute/ml) and 175 mg/m² paclitaxel were randomly assigned to receive 910 mg/m² IV amifostine 30 minutes prior to carboplatin.

• Patients were diagnosed with stage 2–4 ovarian cancer.
• The study reported on a sample of 187 patients (93 in the amifostine group and 94 in the control group).

The study was conducted between April 1999 and July 2001.

This was a phase III, multicenter, randomized trial.

• Grade 3-4 toxicity was reported.
• The National Cancer Institute (NCI) Common Terminology Criteria (CTC) was used.

A significant difference was found in grade 3-4 mucositis (4.7% in the amifostine group versus 15.4% in the control group, p < 0.0001).

• The study was not double blinded.
• The authors did not indicate clearly how mucositis was measured.
• The data in the article was not clear and specific.

Patients in the study group received 910 mg/m² IV amifostine 15–30 minutes prior to  200 mg/m² melphalan prior to autotransplant for multiple myeloma (MM). 

• The study reported on a sample of 90 patients; 43 patients received amifostine, and 47 did not.
• The age range was 31–69 years with a median age of 54 years.

This was a multicenter study conducted between May 1999 and November 2000.

This was an open label, randomized study.

The World Health Organization (WHO) scale for mucositis, median duration of mucositis, duration of total parenteral nutrition (TPN), and duration of narcotics use were recorded.

• Patients in the amifostine group experienced a reduction in median grade of maximal mucositis and incidence of grades 2–4 mucositis compared to the control group. 
• Patients in the amifostine group were more likely to experience no mucositis than patients in the control group, although the difference was not significant.
• Median duration of maximal severity was 3 days in the control group and 4 days in the amifostine group (p = 0.18).
• The control group was more likely to experience severe delayed emesis compared to the amifostine group, although this difference was not significant. 
• No significant differences were found in the requirement for or duration of TPN or narcotics.

This study provided weak statistical evidence for the use of amifostine.

• This study was supported by Schering Plough, which also manufactured amifostine, and Amgen.
• Amifostine infusion toxicities were common in this study.

Patients in the study group received 740 mg/m² IV amifostine prior to 200 mg/m² melphalan.

• The study reported on a sample of 41 patients, out of which 21 received amifostine and 20 were analyzed as controls.
• Patients were diagnosed with stage 3 multiple myeloma (MM) and receiving high-dose 200 mg/m² melphalan and autologous peripheral stem cell transplant.
• Median age of patients was 56 years with a range of 27–68.

This study was conducted betwen September 1999 and December 2001.

This was a prospective, comparative, non-randomized controlled, phase 2 trial conducted at a single institution.

• The World Health Organization mucositis scale was used.
• Opioid use was recorded.
• Delayed gastrointestinal side effects were reported.

• Fewer patients in the amifostine group experienced grade 2–4 mucositis (33% versus 65%, p = 0.047).
• No cases of grade 3-4 mucositis were reported in the amifostine arm.

• The sample size and study population were small.
• A large number of patients experienced emesis (43%).
• Limited mucositis data was included.

To systematically review current evidence for prevention and treatment of gastrointestinal (GI) mucositis in adults and children receiving cancer treatment and to update relevant Multinational Association of Supportive Care in Cancer (MASCC) guidelines

This was an evidence-based guideline developed based on a systematic review of the literature with rating of levels of evidence and identification of study flaws.

Database searched was MEDLINE.

Search keywords were numerous and included all known possible interventions tested.

Inclusion and exclusion criteria were not stated in this article but provided elsewhere in the journal.

• Patients were undergoing the active treatment phase of care.
• The study has clinical applicability for pediatrics.

A total of 1,336 papers were initially retrieved; of these, 146 were reviewed for development of the guidelines.

• Probiotics with Lactobacillus spp. may be beneficial for prevention of chemotherapy- and radiotherapy-induced diarrhea in patients with pelvic malignancies. Two studies with positive results were cited.
• Amifostine may reduce esophagitis because of concomitant radiation and chemotherapy. It is not recommended in other situations because of conflicting evidence.
• Mesalazine, 5-aminosalicylic acid (5-ASA), and olsalazine are not recommended because they have been associated with increased diarrhea compared to placebo.
• Sucralfate is not recommended for diarrhea prevention because it is associated with increased GI side effects, including rectal bleeding.
• Oral sulfasalazine given at 500 mg twice daily is recommended to reduce incidence and severity of radiation-induced enteropathy.
• No guideline was provided for glutamine, but three new studies were sited that showed promising results.
• If loperamide has not resulted in diarrhea control with standard or high-dose chemotherapy in HCTY patients, 100 mcg or greater of subcutaneous octreotide twice daily is recommended.

This review had a limited search strategy, as only one database was searched. In addition, most of the suggestions and recommendations provided were based on low-level evidence by the rating system used.

These guidelines provide some suggestions for management of oral mucositis and diarrhea in patients with cancer. They also provide information regarding evidence for mucositis in the entire GI tract.