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What Should the Optimal Timing Be for Amifostine Administration Relative to Radiation and Chemotherapy?

The University of Texas M.D. Anderson Cancer Center Department of Radiation Oncology, Houston, TX

To the Editor:

The recently published results of Radiation Therapy Oncology Group (RTOG) 98-01 reported a lack of significant cytoprotection with amifostine in patients receiving combined chemotherapy and radiation therapy (RT) for non–small-cell lung cancer.¹ These results should be put into perspective within the context of other trials examining amifostine as a cytoprotectant.

Amifostine administration schedule is an important consideration. Movsas et al cite Fazenbacker et al,² a dosing study in a rodent model, to support the study's dose and dosing regimen. However, Bachy et al,³ using the same model, show the benefit of administering amifostine before each RT dose. In addition, the dose used in the Fazenbacker study was shown by Bachy et al to provide partial protection, while higher doses provided complete protection. While animal data cannot be directly extrapolated to humans, clinical evidence also supports the use of amifostine before each session of RT or chemotherapy. The time interval between RT and amifostine administration is also important. While the prescribing information for amifostine recommends administration 15 to 30 minutes before RT, patients in RTOG 98-01 had a window of 120 to 180 minutes between amifostine and RT on chemotherapy days, potentially reducing the protective effects of amifostine in one fourth of the doses administered.

RTOG 98-01 reported esophagitis as an adverse event rather than a primary end point. In addition, the physicians' and patients' assessments focused on a subjective scoring of dysphagia, whereas the National Cancer Institute Common Toxicity Criteria for radiation-induced esophagitis also includes use of narcotic analgesia. Many trials also report other objective measures, such as the need for feeding tubes or intravenous hydration and hyperalimentation.

Many studies have yielded positive results with amifostine.^4-7 In Leong et al,⁸ amifostine was administered only during induction chemotherapy and not during the ensuing period of RT. Therefore, the differences in the incidence of esophagitis with versus without amifostine (grade 3 esophagitis, 5% v 15%; grades 2 and 3 combined, 43% v 70%) are clinically impressive, though not statistically significant. Senzer⁹ acknowledged that higher doses of amifostine may have been necessary for the combined RT/chemotherapy regimen used and that his data were preliminary rather than definitive. Moreover, he did not explain why the overall incidence of grade 3 or 4 esophagitis (9% with or without amifostine) was much lower than the historic incidence of 40%, on which his statistical model was based.

In conclusion, while RTOG 98-01 is one of the largest studies of amifostine use to date, the methodology of the study may have impacted the results. Therefore, clinicians should consider these limitations when interpreting the results.

Author's Disclosures of Potential Conflicts of Interest

The author or immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Authors Employment Leadership Consultant Stock Honoraria Research Funds Testimony Other Ritsuko Komaki MedImmune Inc (B)

Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C) $100,000 (N/R) Not Required

REFERENCES

1. Movsas B, Scott C, Langer C, et al: Randomized trial of amifostine in locally advanced non-small cell lung cancer (NSCLC) patients receiving chemotherapy and hyperfractionated radiation: Radiation Therapy Oncology Group (RTOG) 98-01. J Clin Oncol 23:2145-2154, 2005[Abstract/Free Full Text]

2. Fazenbaker CA, Bachy CM, Kifle G, et al: Dose and schedule dependency of amifostine protection against hyperfractionated radiotherapy in a rat model. Proc Am Soc Clin Oncol 22:518, 2003 (abstr 2083)

3. Bachy CM, Fazenbaker CA, Kifle G, et al: Daily dosing with amifostine is necessary for full protection against oral mucositis caused by fractionated radiation in rats: Protection and pharmacokinetics. Proc Am Soc Clin Oncol 22:517, 2003 (abstr 2081)

4. Antonadou D, Coliarakis N, Synodinou M, et al: Randomized phase III trial of radiation treatment +/– amifostine in patients with advanced-stage lung cancer. Int J Radiat Oncol Biol Phys 51:915-922, 2001[CrossRef][Medline]

5. Antonadou D, Throuvalas N, Petridis A, et al: Effect of amifostine on toxicities associated with radiochemotherapy in patients with locally advanced non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 57:402-408, 2003[CrossRef][Medline]

6. Koukourakis MI, Kyrias G, Kakolyris S, et al: Subcutaneous administration of amifostine during fractionated radiotherapy: A randomized phase II study. J Clin Oncol 18:2226-2233, 2000[Abstract/Free Full Text]

7. Komaki R, Lee JS, Milas L, et al: Effects of amifostine on acute toxicity from concurrent chemotherapy and radiotherapy for inoperable non-small-cell lung cancer: Report of a randomized comparative trial. Int J Radiat Oncol Biol Phys 58:1369-1377, 2004[CrossRef][Medline]

8. Leong SS, Tan EH, Fong KW, et al: Randomized double-blind trial of combined modality treatment with or without amifostine in unresectable stage III non-small-cell lung cancer. J Clin Oncol 21:1767-1774, 2003[Abstract/Free Full Text]

9. Senzer N: A phase III randomized evaluation of amifostine in stage IIIA/IIIB non-small cell lung cancer patients receiving concurrent carboplatin, paclitaxel, and radiation therapy followed by gemcitabine and cisplatin intensification: Preliminary findings. Semin Oncol 29:38-41, 2002 (suppl 19)

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• In Reply:
  Benjamin Movsas, Charles Scott, Corey Langer, Maria Werner-Wasik, Nicos Nicolaou, Mitchell Machtay, Colum Smith, Rita Axelrod, Linda Sarna, Todd Wasserman, and Roger Byhardt
  JCO 2005 23: 7233-7235 [Full Text]

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