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

This retrospective study investigates if delays between the diagnosis of cancer of the oesophagus and surgical resection influence long-term survival. Data held by the West Midlands Cancer Intelligence Unit on 800 patients who underwent oesophagectomy for a diagnosis of cancer of the oesophagus or oesophagogastric junction between 1995 and 2000 were reviewed. Six hundred and thirtytwo patients treated with curative intention and who had not received neo-adjuvant treatment in the form of radio-or chemotherapy were included in the analysis. The time interval between histological diagnosis and surgical resection was stratified into four groups: less than 3, 3 -6, 6 -9 and more than 9 weeks. The Cox proportional hazard model was used to test for the independent effect of delays. The results showed no difference in long-term survival according to the delay between histological diagnosis and surgical resection. On multivariate analysis adverse prognostic factors were advanced age, incomplete resection and lymph node involvement. Patients with a longer delay had a higher rate of complete tumour resection suggesting that they were more appropriately selected for the surgical treatment approach. In conclusion we have found no evidence that shorter delays from the date of histological diagnosis to surgical resection are beneficial to long-term survival.

Positron emission tomography studies with oxygen-15 -labeled water provide in vivo quantitative tissue perfusion variables-blood flow and fractional volume of distribution of water [V d (water)]. To investigate the relationship between perfusion variables and the effect of vasculartargeting agents on vasculature, we measured tissue perfusion in tumors, spleen, kidney, and liver before and after treatment with combretastatin-A4-phosphate, a combination of nicotinamide and carbogen (N/C), and interferon (IFN). We observed that mean tumor blood flow and V d (water) was lower than in kidney, liver, and spleen at baseline. Blood flow and V d (water) were related in tumor (r = 0.62; P = 0.004) at baseline, but not in other normal tissues evaluated, where minimal variations in V d (water) were observed over a wide range of blood flow. Despite the relationship between blood flow and V d (water) in tumors before intervention, vascular-targeting agentinduced changes in these perfusion variables were not correlated. In contrast, changes in blood flow and V d (water) correlated in kidney and spleen after N/C and in kidney after combretastatin-A4-phosphate. The close relation between blood flow and V d (water) in tumors but not normal tissue may reflect barriers to fluid exchange in tumors because of necrosis and/or increased interstitial fluid pressure and underlies the importance and interdependence of these positron emission tomography perfusion variables under these conditions. As blood flow and V d (water) signify different aspects of tissue perfusion, the differential effects of interventions on both variables, flow and V d (water), should therefore be reported in future studies. [Mol Cancer Ther 2009;8(2):303 -9]

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