Increased blood flow to human rectal cancer induced by nelfinavir and radiotherapy


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Esme Hill1,2, Jamie Franklin2, Mike Partridge1, Somnath Mukherjee1,2, Jun Li1, Kwun-Ye Chu2, Mark Anderson1,2, Ricky Sharma1,2
1University of Oxford, Oxford, UK, 2Churchill Hospital, Oxford, UK

Background

In preclinical models, nelfinavir, an inhibitor of Akt in the PI3-kinase signalling pathway, is an intrinsic radiosensitiser which increases tumour blood flow and reduces hypoxia. We conducted apilot study of nelfinavir and short-course pelvic radiotherapy (SCRT) in patients with metastatic rectal cancer to explore changes in tumour perfusion during therapy using perfusion Computed Tomography (pCT).

Method

Eight patients with T3-4 N1-2 M1 rectal cancer received 25 Gy in 5 fractions in 7 days to the pelvis; nelfinavir 1250 mg bd PO was given for 7 days before and 7 days concomitant with RT. pCT scans of the pelvis were performed pre-treatment, on the seventh day of nelfinavir and on the last day of radiotherapy and nelfinavir. Blood Volume (BV), Blood Flow (BF) and Mean Transit Time (MTT) were derived within the tumour region of interest (ROI) on 8 pCT slices using proprietary software (CT Perfusion 3, GE). CT images were used to identify slices from comparable anatomical levels in the pelvis on sequential scans and the mean of the parameter values from those slices was calculated.

Results

All patients completed 3 pCT scans. One patient was excluded from analysis due to technically inadequate scans. On analysis of evaluable scans at baseline and after 7 days of nelfinavir, no statistically significant change was demonstrated. Between the second and third scans there was a median 30% increase in BF (P=0.028) and 24.0% decrease in MTT (P=0.018) [Wilcoxon Signed Ranks Test]. Of note, BF increased in all patients except one, who had progressive disease on pelvic MRI 8 weeks post-SCRT.

Conclusion

SCRT with concurrent nelfinavir results in increased BF and reduced MTT in rectal cancer, indicating improved tumour perfusion. This study is the first to demonstrate an increase in rectal tumour BF on pCT during radiotherapy.