H. Sleiman1, L. Meske1, W. Culberson2, J. Micka2, E. Carchman1 1University Of Wisconsin,General Surgery,Madison, WI, USA 2University Of Wisconsin,Department Of Medical Physics,Madison, WI, USA
Introduction: Chemoradiotherapy is the current standard of care for patients with anal cancer1. The 5 year survival rates of patients with localized disease after chemoradiotherapy is approximately 65%, with 1/3 of these patients developing disease recurrence. The survival rates are significantly less in patients with locally advanced or metastatic disease treated with standard of care. Finally, the toxicity associated with chemoradiotherapy regardless of stage, is not insignificant with 30% of the patients requiring colostomy creation due to therapy related side-effects. Unfortunately there have been no changes in the treatment for anal cancer over the last 4 decades, largely in part to a lack of preclinical models. This project describes the first mouse preclinical model for anal cancer therapy with treatment responses mirroring those seen in humans.
Methods: K14E6/E7 (expressing HPV-16 oncoproteins in their epithelium) mice were utilized and anuses treated with 7,12-Dimethylbenz[a]anthracene (DMBA) topically until squamous cell carcinoma of the anus developed. The study contained four treatment groups: no-treatment controls (7 mice), radiotherapy alone-2 Gy (5 mice), chemotherapy alone- mitomycin C and 5-flourauracil (3 mice), and chemoradiotherapy (4 mice). The Xoft® Axxent eBx® system, consisting of an x-ray tube within a cone-shaped skin applicator, was used to irradiate anal tumors to a depth of 3mm at a known absorbed dose. Anal tumors were measured at three dimensions (mm3) on a daily basis until mice died or met criteria to be removed from the study (22-day treatment time period). All mice tumor sizes were normalized to 0 at day 0 and changes in tumor size over time noted. Groups were then compared using one-way ANOVA.
Results: Treatment Response: Within 16 days of initiating chemoradiotherapy there was noted to be a significant treatment response compared to no-treatment controls (p-value<0.05). This treatment response was noted, to a lesser degree, in mice that recieved chemotherapy alone. Please refer to graph 1 for average tumor volume changes over time. Survival Times: Mice that received no treatment survived on average 30 days with signficant growth rates of anal tumors. Mice that received radiation alone survived on average 22 days without significant growth rates of anal tumors, but died of complications due to tumors outside of the anus. Mice that received chemotherapy or chemoradiotherapy survived to the 48 day endpoint.
Conclusion:We have generated a HPV mouse model of anal cancer treatment that mimics responses seen in the humans with chemoradiotherapy. This model can be utilized to test new therapies with the hope of improving response rates and decreasing toxicity in anal cancer treatment.
