Carbogen and nicotinamide increase blood flow and 5-fluorouracil delivery but not 5-fluorouracil retention in colorectal cancer metastases in patients.
OBJECTIVE
To examine whether carbogen and nicotinamide increases 5-fluorouracil (5-FU) delivery to colorectal cancer metastases.


METHODS
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 (m(2)/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.


CONCLUSIONS
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.
Gupta
Nishi
N
Cancer Research UK PET Oncology Group and Hammersmith Imanet, Hammersmith Hospital NHS Trust, London, United Kingdom.
Saleem
Azeem
A
Kötz
Barbara
B
Osman
Safiye
S
Aboagye
Eric O
EO
Phillips
Robert
R
Vernon
Clare
C
Wasan
Harpreet
H
Jones
Terry
T
Hoskin
Peter J
PJ
Price
Patricia M
PM
D000280:Administration, Inhalation; D000284:Administration, Oral; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000493:pharmacokinetics*; D002245:Carbon Dioxide / Q000494:pharmacology*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004347:Drug Interactions; D005260:Female; D005472:Fluorouracil / Q000493:pharmacokinetics*; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000556:secondary; D008297:Male; D008875:Middle Aged; D009536:Niacinamide / Q000494:pharmacology*; D010100:Oxygen / Q000494:pharmacology*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D012039:Regional Blood Flow; D014018:Tissue Distribution; D014803:Vitamin B Complex / Q000494:pharmacology*
D000964:Antimetabolites, Antineoplastic; D011838:Radiation-Sensitizing Agents; D014803:Vitamin B Complex; D002245:Carbon Dioxide; D009536:Niacinamide; C011700:carbogen; D010100:Oxygen; D005472:Fluorouracil