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Carbogen and Nicotinamide Increase Blood Flow and 5-Fluorouracil Delivery but not 5-Fluorouracil Retention in Colorectal Cancer Metastases in Patients

Authors' Affiliations: ¹ Cancer Research UK PET Oncology Group and Hammersmith Imanet, Hammersmith Hospital NHS Trust, London; ² Wolfson Molecular Imaging Centre, University of Manchester, Manchester, United Kingdom; and ³ Mount Vernon Hospital, Northwood, Middlesex

Requests for reprints: Pat Price, University of Manchester, Wolfson Molecular Imaging Centre, 27 Palatine Road, Manchester M20 3LJ, United Kingdom. Phone: 44-161-446-8003; Fax: 44-161-446-8111; E-mail: pat.price{at}manchester.ac.uk.

Purpose: To examine whether carbogen and nicotinamide increases 5-fluorouracil (5-FU) delivery to colorectal cancer metastases.

Experimental Design: Six patients were scanned using positron emission tomography. Two scans were done to coincide with the start of separate chemotherapy cycles. At the second positron emission tomography session, 60 mg/kg nicotinamide was given orally 2 to 3 hours before 10-minute carbogen inhalation. In the middle of carbogen treatment, [¹⁵O]H₂O (to measure regional tissue perfusion) and then [¹⁸F]5-FU (to measure 5-FU tissue pharmacokinetics) were administered.

Results: Regions of interest were drawn in 12 liver metastases, 6 spleens, 6 livers, and 12 kidneys. Nicotinamide and carbogen administration increased mean blood pO₂ from 93 mm Hg (95% confidence interval, 79-198) to 278 mm Hg (95% confidence interval, 241-316; P = 0.031). Regional perfusion (mL_blood/min/mL_tissue) increased in metastases (mean change = 52%, range –32% to +261%, P = 0.024), but decreased in kidney (mean change = –42%, range –82% to –11%, P = 0.0005) and liver (mean change = –34%, range –43% to –26%, P = 0.031). 5-FU uptake at 3.75 minutes (m²/mL) increased in tumor (mean change = 40%, range –39% to +196%, P = 0.06) and decreased in kidney (mean change = –25%, range –71% to 12%, P = 0.043). 5-FU delivery measured as K₁ increased in tumor (mean change = 74%, range –23% to +293%, P = 0.0039). No differences were seen in [¹⁸F]5-FU tumor exposure (net area under curve) and retention.

Conclusion: Nicotinamide and carbogen administration can increase 5-FU delivery to colorectal cancer liver metastases. Despite an increase in perfusion and 5-FU delivery, the effects were not directly related and did not increase 5-FU retention or tissue exposure.

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