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, [ 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 À32% to +261%, P = 0.024), but decreased in kidney (mean change = À42%, range À82% to À11%, P = 0.0005) and liver (mean change = À34%, range À43% to À26%, P = 0.031). 5-FU uptake at 3.75 minutes (m 2 /mL) increased in tumor (mean change = 40%, range À39% to +196%, P = 0.06) and decreased in kidney (mean change = À25%, range À71% to 12%, P = 0.043). 5-FU delivery measured as K 1 increased in tumor (mean change = 74%, range À23% to +293%, P = 0.0039). No differences were seen in [ Although 5-fluorouracil (5-FU) dominates the chemotherapy of colorectal cancer, the response rate of advanced disease to the drug given as a single agent is only around 15% (1, 2). This poor response rate has stimulated research into approaches for increasing its therapeutic index, such as biochemical modulation (e.g., using folinic acid; ref. 1) and schedule alteration (e.g., continuous infusions rather than bolus administration, oral administration; ref. 2). The rationale behind changing the mode of 5-FU administration relates to its short biological half-life (10-20 minutes) and its S-phase-dependent activity, which limit the systemic exposure of drug and tumor cell kill (3, 4). Increasing the plasma levels of 5-FU can improve response and survival in patients (5, 6). However, additional improvements in 5-FU efficacy by increasing plasma drug levels are further limited by dose-limiting normal tissue toxicity, and other approaches for enhancing the efficacy of 5-FU are required.It is postulated that the administration of nicotinamide and carbogen to patients with metastatic colorectal cancer should selectively increase the uptake of 5-FU into a tumor, by increasing tumor blood flow, without changing the systemic exposure to the drug. The nicotinamide and carbogen combination is being explored as an approach for reducing tumor hypoxia, an important cause of cancer treatment resistance (7), and improving radiotherapy response (8 -11). Nicotinamide, an amide of vitamin B 3 , can increase tumor blood flow via a mechanism thought to involve the stabilization of the tumor microvasculature (reducing contractility and fluctuations in blood flow; refs. 12, 13) and a decrease in Cancer Therapy: Clinical