Final Results of a Phase I Whole-Liver Radiation Dose Escalation Trial using Amifostine as a Radioprotector

Article Outline

• Purpose/Objective(s)
• Materials/Methods
• Results
• Conclusions
• Copyright

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Purpose/Objective(s) 

We have previously shown, in a series of phase I/II studies, that high-dose radiation therapy is effective for focal liver involvement. However, normal liver tolerance limits effective irradiation of the whole liver. Amifostine is a prodrug free-radical scavenger that has selective affinity to normal tissues, and in a preclinical model of intrahepatic cancer, systemic Amifostine can reduce normal liver radiation damage by up to 50%, without compromising the effect on the cancer (Symon Z, et al. Int J Radiat Oncol Biol Phys. 50:473, 2001). This phase I, IRB-approved study was designed to assess the maximum tolerated dose (MTD) of whole liver radiation with the protection of Amifostine.

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Materials/Methods 

Patients >18yo, with diffuse, unresectable liver cancer, that had not received prior radiation to the liver were eligible for this study. Based on our previous findings that liver tolerance is lower in patients with primary cancer compared to patients with metastatic disease, radiation dose was escalated independently in these two groups. Amifostine 340mg/m² was delivered intravenously daily, 15-30 minutes prior to whole liver XRT (2Gy per fraction, 5 days a week). The Time-to-Event Continual Reassessment Method is used to assign the radiation doses. The patients were evaluated for acute, sub-acute and late toxicity. A CT or MRI was obtained 2 months after treatment to assess response.

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Results 

A total of 23 patients were accrued, 16 with primary cancer and 7 with metastatic disease. There were 11 female and 12 male patients. Median age was 60.4 years (35.2 to 78.0 years). The last dose tested in patients with primary cancer was 36 Gy; the maximum dose tested was 40 Gy. Treatment of patients with metastatic cancer was halted due to unexpected toxicity related to prior alkylating chemotherapy. Based upon the dose levels treated, the estimated probabilities of toxicity for patients with primary cancers equals 0.14 at 36Gy [90% prediction interval = (0.11, 0.17)], 0.21 at 37 Gy [90% PI = (0.16, 0.24)], and 0.29 at 38 Gy [90% PI = (0.22, 0.32)]. Radiation-induced-liver-disease developed in 2 primary (40Gy and 38Gy) and 2 metastatic (both 36Gy) cancer patients. Tumor responses of all patients at 2 months were 2 with PR, 8 with SD, 13 with PD, which does not differ substantively from our previous experience with whole liver radiation.

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Conclusions 

Escalated doses of radiation to the whole liver for patients with primary liver cancer can be administered beyond commonly accepted whole liver tolerance with Amifostine, up to 37 Gy, without obvious tumor protection. This suggests that Amifostine may be a useful normal liver radiation protector for patients undergoing focal liver radiation.

Supported by RO1 CA098502 and a grant from MedImmune.