Equivalent Cyclophosphamide Efficacy Against Leukemia in Mice Treated with Topical Vasoconstrictors

BACKGROUND:

Chemotherapy and radiation therapy-induced oral mucositis (OM) causes significant morbidity including pain, infection, poor nutrition, and rarely, upper airway compromise. Alopecia is rated as one of the top causes of distress from cancer therapy. Fahl et al. showed that alopecia was prevented in animals by applying topical epinephrine or norepinephrine prior to radiation or chemotherapy. They also demonstrated that animals receiving oro-topical phenylephrine (PhE) prior to radiation had improved weight gain and decreased inflammation of the oral mucosa. Vasoconstrictive techniques (i.e., cryotherapy) have shown modest success, but compliance can be challenging and most modalities have not been rigorously tested. Concern has been expressed that vasoconstrictive methods to prevent alopecia and OM may decrease chemotherapy delivery to tissues, thereby creating a sanctuary site for untreated cancer cells. The primary objective of this study was to compare survival of mice with leukemia who were given topical vasoconstrictors prior to receiving chemotherapy to animals who did not receive vasoconstrictors.

METHODS

B6D2F1 mice received 10^4 L1210 cells (mouse leukemia strain) via retro-orbital injection. Group A received L1210 cells with no further treatment. All other groups received a single intra-peritoneal (IP) 90 mg dose of cyclophosphamide (sub-curative) 24 hours after injection with L1210 cells. Group B did not receive a vasoconstrictor. Groups C through G had their fur clipped and were given increasing doses of topical epinephrine (epi) 15 minutes prior to cyclophosphamide. Groups H through M were given increasing doses of oro-topical phenylephrine 15 minutes prior to cyclophosphamide. All mice were followed until date of death. P-values and hazard ratios were calculated comparing median survival of groups C-M with Group B (see table)

RESULTS

Differences in median survival between Group B mice and all other mice who received cyclophosphamide and oro-topical phenylephrine or topical epinephrine were not statistically significant.

CONCLUSIONS:

Administration of topical vasoconstrictors to mice with leukemia did not affect survival following administration of cyclophosphamide. A Phase I/IIa dose escalation trial evaluating safety and efficacy of oro-topical phenylephrine in human subjects undergoing SCT conditioning with cyclophosphamide plus total body irradiation (TBI) is in progress. Preliminary data indicate that application of oro-topical PhE is feasible and well-tolerated. This may provide a cost-effective and convenient method of preventing OM in susceptible patients. If minimal phenylephrine systemic absorption after oral-topical application is demonstrated, future studies will focus on enrollment of pediatric patients.