Amifostine

Amifostine

PEP Topic 
Chemotherapy-Induced Diarrhea
Description 

Amifostine is a cytoprotective agent that can protect DNA and RNA from the damage of chemotherapeutic agents that involve binding to DNA, such as platinum-containing and alkylating agents. It also may accelerate DNA repair and protect cells against the harmful effects of radiation treatment. Amifostine is administered intravenously. Amifostine has been studied for its effects on diarrhea, mucositis, and peripheral neuropathy.

Benefits Balanced With Harm

Research Evidence Summaries

Tsavaris, N., Kosmas, C., Vadiaka, M., Zonios, D., Papalambros, E., Papantoniou, N., … Koufos, C. (2003). Amifostine, in a reduced dose, protects against severe diarrhea associated with weekly fluorouracil and folinic acid chemotherapy in advanced colorectal cancer: A pilot study. Journal of Pain and Symptom Management, 26(3), 849–854.

doi: 10.1016/S0885-3924(03)00283-5
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Intervention Characteristics/Basic Study Process:

Patients with colorectal cancer who experienced persistent diarrhea with fluorouracil (5-FU) and calcium folinate infusion despite dose reductions were treated with 800 mg/m2, 500 mg/m2, or 150 mg/m2 amifostine. Amifostine works by selectively protecting normal but not tumor tissues from cytotoxic effects of radiation therapy and chemotherapy.

Sample Characteristics:

  • The study reported on 52 consecutively recruited patients with colorectal cancer.
  • To be eligible, patients must have
    • Had advanced metastatic or Dukes stage B2 or C colorectal cancer. 
    • Developed grade 3 and 4 or persistent grade 2 diarrhea (according to World Health Organization [WHO] classification) despite 10%–20% reduction in chemotherapy dose.
    • Been receiving adjuvant chemotherapy with 500 mg/m2 5-FU plus 50–100 mg/m2 calcium folinate weekly. 
  • With diarrhea recurrence, patients were assigned to one of three groups.
    • Group I (n = 18) received 800 mg/m2 amifostine weekly.
    • Group II (n = 16) received a lowered dose of 500 mg/m2 amifostine weekly.
    • Group III (n = 18) received a lowered dose of 150 mg/m2 amifostine weekly.

Measurement Instruments/Methods:

  • Continuous outcomes were compared using paired t-test (comparisons with baseline) or the independent sample t-test (between groups). Changes in heme parameters were analyzed using dichotomous (binary) variables of “decrease” or “increase.”
  • Paired comparisons used the McNemar test; independent comparisons used Pearson’s chi-square.
  • The primary endpoint was the proportion of 5-FU/calcium folinate doses associated with diarrhea or amifostine toxicity.
  • Secondary endpoints were patient reports of chemotherapy-related adverse effects such as mucositis, anorexia, nausea and vomiting, and hematologic toxicity.

Results:

  • The mean number of cycles of chemotherapy administered prior to amifostine was 6.55 (SD = 2.83). The median number of cycles was 9, and the range was 5–17.
  • Incidence of diarrhea (using WHO classification) during baseline phase (n = 52) was as follows.
    • Degree 0: 9.9 %
    • Degree 1: 52%
    • Degree 2: 24.4 %
    • Degree 3: 9.9 %
    • Degree 4: 3.8 %
  • All patients received diphenoxylate or loperamide to control diarrhea, 12 also were treated with octreotide until resolution of diarrhea, and seven were readmitted for dehydration.
  • Compared with baseline, all doses of amifostine significantly reduced incidence of diarrhea (p < 0.0001 for each group). Amifostine was also found to be beneficial in decreasing mucositis (p < 0.04).
  • No differences were found between groups regarding severity of diarrhea.
  • A statistically significant difference (p < 0.04) was found in the mean number of administered doses of 5-FU between patients before and after treatment with amifostine. No significant difference was found between mean 5-FU doses during treatment with amifostine.
  • A high incidence of adverse events was reported in group 1 (76.3%) despite complete resolution of grade 3–4 or persistent grade 1–2 5-FU-related diarrhea. The primary adverse effect was hypotension (0% at baseline in all groups), which was 76% in group 1, 54% in group 2, and 25% in group 3.

Conclusions:

Although previous studies have found that doses of amifostine between 740–910 mg/m2 are effective, this study suggested that lower doses may be effective and increase tolerability. The study suggested that 20% of the usual dose of amifostine is capable of offering adequate protection against diarrhea and mucositis associated with 5-FU. Although the 500 mg/m2 and 800 mg/mdose levels were equally effective in decreasing the risk of all grades of diarrhea, the lower dose was better tolerated. The 150 dose level was the best tolerated and was nearly as effective as higher doses in preventing severe and grade 1 diarrhea. Amifostine appears to offer protection against gastrointestinal adverse effects and permit higher doses of 5-FU.

Limitations:

  • Amifostine side effects include hypotension, nausea, vomiting, chills, and dizziness.
  • The study used WHO grading rather than the more common National Cancer Institute (NCI) Common Toxicity Criteria (CTC).
  • The authors did not state the total dose of loperamide and other pharmacologic interventions used.
  • No parallel nontreatment randomized control group was included, so the authors stated the results should not be “regarded as definitive.”

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