Carbogen

Abstract: Purpose : “ARCON” combines accelerated radiotherapy to counteract tumor repopulation with carbogen breathing and nicotinamide to reduce chronic and acute hypoxia. The aim of this Phase II study was to assess the feasibility, toxicity, and potential effectiveness of ARCON for advanced head-and-neck cancer. Methods and Materials : The study included 215 patients with head-and-neck carcinoma distributed as follows: larynx, n = 100; hypopharynx, n = 50; oropharynx, n = 52; oral cavity, n = 13; Stage II, n = 8, Stage III, n = 71, and Stage IV, n = 136. Accelerated radiotherapy was given to a total dose of 64–68 Gy in 2-Gy fractions within 36–38 days. This was combined with carbogen breathing during irradiation and administration of nicotinamide (60–80 mg/kg) 1–1.5 h before irradiation. Results : There was full compliance with carbogen breathing in 88% of the patients. A nicotinamide dose of 80 mg/kg produced severe nausea and vomiting, necessitating discontinuation of the drug, in 31% of the patients. Adjustment of the dose to 60 mg/kg and antiemesis prophylaxis reduced the discontinuation rate to 10%. Confluent mucositis was observed in 91% of the patients with a median duration of 6 weeks. Grade 4 late complications occurred in 5% of the patients. The actuarial 3-year local control rates were 80% for larynx, 69% for hypopharynx, 88% for oropharynx, and 37% for oral cavity tumors. For T3–4 tumors, the local control rates were 80% for larynx, 60% for hypopharynx, 87% for oropharynx, and 29% for oral cavity. Regional control rates were 100% for N0, 93% for N1, and 74% for N2 disease. Conclusion : ARCON yields high local and regional control rates in advanced head-and-neck carcinomas, and compliance is satisfactory and morbidity acceptable. The local control rate of 80% for T3 and T4 larynx carcinomas offers excellent possibilities for organ preservation.

Abstract: An MRI method is described for demonstrating improved oxygenation of human tumors and normal tissues during carbogen inhalation (95% O2, 5% CO2). T2*-weighted gradient-echo imaging was performed before, during, and after carbogen breathing in 47 tumor patients and 13 male volunteers. Analysis of artifacts and signal intensity was performed. Thirty-six successful tumor examinations were obtained. Twenty showed significant whole-tumor signal increases (mean 21.0%, range 6.5-82.4%), and one decreased (-26.5 +/- 8.0%). Patterns of signal change were heterogeneous in responding tumors. Five of 13 normal prostate glands (four volunteers and nine patients with nonprostatic tumors) showed significant enhancement (mean 11.4%, range 8.4-14.0%). An increase in brain signal was seen in 11 of 13 assessable patients (mean 8.0 +/- 3.7%, range 5.0-11.7%). T2*-weighted tumor MRI during carbogen breathing is possible in humans. High failure rates occurred due to respiratory distress. Significant enhancement was seen in 56%, suggesting improved tissue oxygenation and blood flow, which could identify these patients as more likely to benefit from carbogen radiosensitization.

Abstract: Fluorine-19 inversion-recovery, echo-planar imaging (IR-EPI) was used in conjunction with a new PFC emulsion, perfluoro-15-crown-5-ether, to map the spatial distribution of oxygen tension in murine liver, spleen and radiation induced fibrosarcoma (RIF-1) tumors. Intravenously administered PFC emulsions were allowed to sequester in the liver, spleen, and tumor 3 to 7 days prior to imaging experiments. Seven, 64 x 64 IR-EPIs were acquired with successively increasing inversion times (TI). A nonlinear least-squares regression algorithm was used to fit the seven two-dimensional matrices, on a pixel-by-pixel basis, to solve for the relaxation rate, R1, of the sequestered PFC. From in vitro calibration curves, the oxygen tension (pO2) was calculated from the measured R1. Oxygen tension maps were then murine liver and spleen were produced (in 2.5 min) to demonstrate the technique and changes in tissue oxygenation as a function of breathing gas (air and carbogen (95% O2-5% CO2)) are presented. Tissue pO2 maps from RIF-1 tumors (n = 5) were obtained in less than 10 min and changes in tumor pO2 were studied when the breathing gas was switched from air to carbogen. The results from tumor pO2 maps were compared with 19F MR spectroscopy measurements to check for consistency. Histogram analysis yielded an average liver and spleen pO2 of 43 torr and 26 torr for RIF-1 tumors when the animals were breathing air. Statistically significant changes in tumor oxygenation as a function of breathing gas were obtained from both pO2 maps (6 +/- 2 torr, P < 0.05) and 19F MR spectroscopy (13 +/- 3 torr, P < 0.01) as evaluated using the Student's paired t test.