PRELIMINARY-RESULTS OF A PILOT-STUDY USING WR-2721 BEFORE FRACTIONATED-IRRADIATION OF THE HEAD AND NECK TO REDUCE SALIVARY-GLAND DYSFUNCTION

Purpose: Based on in vivo evidence of radioprotection of the salivary glands using WR-2721, a pilot study was undertaken to determine the fe asibility, toxicity, and salivary function of patients receiving WR-27 21, while undergoing radiation therapy to the head and neck. Methods a nd Materials: Patients undergoing radiation therapy for cancer of the head and neck were eligible if the major salivary glands received more than 45 Gy. WR-2721 was administered over 6 min IV, 10-15 min prior t o each dose of radiation five times per week. Saliva was collected and measured prior to radiation therapy, weekly during radiation therapy, 1 month postradiation therapy, and every 3 months thereafter. Flow ra tes of unstimulated whole saliva, stimulated whole saliva, and stimula ted parotid saliva were measured using standard techniques. Tc-99m sal ivary scintiscans were performed prior to radiation therapy, 1 month p ostradiation therapy and every 3 months thereafter. Nine patients are presently enrolled on the first dose level (100 mg/m(2)) of this study . Eight completed per protocol, two with minor decreases of total WR-2 721 doses. Two patients progressed with distant metastases soon after completion of therapy. All available data are included in the analysis . Median follow-up for all patients is 18 months. Results: Flow rates of unstimulated whole saliva decreased significantly during radiation therapy reaching 5.6% of baseline at 9 months postradiation therapy, s ubsequently recovering to 20% of baseline, then remaining stable over time. Stimulated whole salivary flow rate similarly decreased during r adiation therapy and reached its nadir (11% of baseline) at 3 months p ostradiation therapy, improving to 27% of baseline by 2 years. The sti mulated parotid flow rate decreased during radiation therapy to 1.4% o f pretreatment levels. Significant recovery took place 6 months postra diation therapy and by 18 months values had recovered to 54% of baseli ne. Tc-99m salivary scintiscans confirmed this rebound of parotid func tion postradiation therapy. Toxicity was minimal with the exception of one patient who received only 27% of the planned total drug dose due to grade 3 hypotension after the eighth treatment. No recovery of sali vary function has been seen in this patient; flow rates remain zero in all three areas tested 21 months after radiation. Conclusions: Admini stration of WR-2721 prior to each dose of radiation was feasible and w ithout significant toxicity at 100 mg/m(2). Salivary gland function im proved over time after completion of radiation, particularly the parot id. Future directions include escalation of WR-2721 dose to 200 mg/m(2 ) and then 300 mg/m(2), and a Phase III randomized trial will be under taken once the optimal dose is established.