An MRI method is described for demonstrating improved oxygenation of human tumors and normal tissues during carbogen inhalation (95% O 2 , 5% CO 2 ). T* 2 -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%). T* 2 -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.

The gas mixture carbogen may be breathed by patients to enhance the oxygenation level and therefore the radiosensitivity of tumours. However, owing to the high CO2 content, its inhalation is associated with patient intolerance. Our aim was to determine a suitable carbon dioxide and oxygen gas mixture with similar enhancement of arterial oxygenation to 5% carbogen and with improved patient tolerance. 14 patients entered the study; of those 14, 8 were able to tolerate 2%, 3.5% and 5% carbogen mixtures as well as a control gas for sufficient time to allow successful arterial blood gas sampling. Gas exchange parameters were measured using a carbon dioxide monitor and a blood gas analyser. Arterial carbon dioxide tension ranged from 2.9 kPa to 6.82 kPa whilst breathing the carbogen mixtures, and arterial oxygen tension increased at least three-fold from basal values. There were no significant changes in the respiratory rate, heart rate and blood pH. The results suggest that 2% CO2 in O2 enhances arterial oxygen levels to a similar extent as 3.5% and 5% CO2 and that it is well tolerated.

Summary Carbogen and nicotinamide have been evaluated in a phase 11 study as hypoxia-modifying agents during radical radiotherapy for bladder cancer using a standard daily 20-fraction schedule. Three groups of patients have received (a) nicotinamide alone, given orally in a dose of 80 mg kg-1 daily with 52.5 Gy in 20 fractions over 4 weeks, (b) carbogen alone, with 50 Gy in 20 fractions over 4 weeks, and (c) carbogen and nicotinamide, with 50-52.5 Gy in 20 fractions over 4 weeks. Ten patients were treated in each group. All patients completed carbogen and radiotherapy as prescribed, but only 45% completed daily nicotinamide over the 4-week treatment period. The end points of this study were acute bowel and bladder morbidity and local control at cystoscopy 6 months after treatment. An expected level of acute bowel and bladder morbidity was seen that reverted to normal in most patients by 12 weeks with no difference between the three treatment groups.Complete response rates at 6 months were seven out of ten (100%) in the nicotinamide alone group, nine out of ten (90%) in the carbogen alone group and seven out of ten (70%) in the carbogen and nicotinamide group. It is concluded that carbogen and nicotinamide may improve the results of daily fractionated radiotherapy in bladder cancer and that further evaluation is required.Keywords: bladder cancer; hypoxia; nicotinamide; carbogen Radical radiotherapy is an important treatment for the management of muscle-invasive (T2, T3) and high-grade superficial (TIG3) bladder cancer. It is not, however, universally effective, and 5-year survival ranges from 30% to 50%, with local failure being a major predictor of survival (Hope-Stone et al, 1981;Duncan and Quilty, 1986). A dose-response relationship for bladder carcinoma has been demonstrated using a hyperfractionated schedule to 84 Gy, but even in this series, despite a 62% complete remission rate at 6 months, the 5-year survival was only 37% (Edsmyr et al, 1985).Possible mechanisms of radioresistance may include hypoxia, repopulation and intrinsic radioresistance. The limited data available have shown that bladder cancer has a median potential cell-doubling time of 17 days (Rew et al, 1991), which suggests that repopulation is probably not a major feature in the failure of radiotherapy to control bladder cancer. Intrinsic radioresistance might be expected to be modified by dose escalation, and this has been demonstrated in the data quoted above. Despite dose escalation, however, a significant failure rate was still seen, and 38% of patients failed ever to achieve local control. This implies that hypoxia may also be important in the control of bladder cancer. Previous studies of hyperbaric oxygen and carbogen have been unsuccessful in improving response rates relative to control arms without hypoxic modification, but these studies can be criticized in terms of the dose fractionation schedules employed (Cade et al, 1978) or the means of carbogen administration (Keresteci and Rider, 1973).In experimental models, there is eviden...

BACKGROUND Accelerated radiotherapy combined with carbogen and nicotinamide (ARCON) to overcome tumor hypoxia and cell proliferation achieved high tumor control and survival in Phase II studies of patients with advanced head and neck and bladder carcinomas. Thus, morbidity and treatment outcomes from the latter study were analyzed to evaluate the therapeutic potential of ARCON. METHODS Acute and late morbidity was assessed in 105 patients with high‐grade superficial or muscle‐invasive bladder carcinoma who were given accelerated radiotherapy (50–55 grays in 4 weeks) with carbogen alone or with ARCON. Urinary dysfunction was scored based on daytime frequency, nocturia, incontinence, dysuria, hematuria, and urgency. Bowel morbidity was based on stool frequency and consistency, rectal discharge, blood loss, and medication. Endpoints for treatment outcome were overall survival, disease‐free survival, and locoregional control. RESULTS Nearly all patients experienced reduced ability to retain urine beyond 2 hours, although 20–30% had almost normal function at night. Incidence of acute moderate or worse dysuria was 41% with ARCON and 56% with carbogen; 96% and 76% of patients, respectively, had bowel frequencies ≥ 3 times per day. By 10–12 weeks from the start of radiotherapy, acute reactions returned to baseline levels. At 3 years, the daytime frequency ≤ 2 times per hour was ≈ 75% in both arms. Incidence of severe hematuria (≤ 25%) and urinary urgency (≤ 16%) was much lower. No more than 6% of patients had severe bowel morbidity. With most assays, the differences between schedules were not significant either for acute or late morbidity. Local tumor control and survival rates at 3 years were 53% and 43%, respectively, for ARCON, similar to the rates for carbogen alone. CONCLUSIONS Historical comparisons suggested no overt increase in normal tissue radiosensitivity when adding carbogen and nicotinamide. Although, for some endpoints, the incidence of late sequelae was higher than expected, overall morbidity was no worse than reported by others. The data indicated that ARCON could achieve a therapeutic gain in patients with advanced bladder carcinoma. A Phase III, randomized, multicenter trial is underway currently in the United Kingdom to evaluate these findings. Cancer 2005. © 2005 American Cancer Society.