Melanie E.B. Powell

BOLD MRI of human tumor oxygenation during carbogen breathing

An MRI method is described for demonstrating improved oxygenation of human tumors and normal tissues during carbogen inhalation (95% O2, 5% CO2). 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. J. Magn. Reson. Imaging 2001;14:156–163.

The response of human tumors to carbogen breathing, monitored by gradient-recalled echo magnetic resonance imaging

PURPOSE Gradient-Recalled Echo (GRE) Magnetic Resonance Imaging (MRI), which detects changes in blood vessel deoxyhaemoglobin content, has been investigated as a noninvasive monitor of changes in human tumor oxygenation and blood flow, in response to carbogen (95% O2, 5% CO2) breathing. METHODS AND MATERIALS GRE images (TE = 60 ms, TR = 200 ms, alpha = 40 degrees, 256[2] matrix) were acquired from 31 patients with primary and metastatic disease, prior to and during carbogen breathing. Three patients underwent a follow-up examination after radiotherapy. RESULTS Seventeen out of 34 tumors showed enhanced image intensity, consistent with an improvement in tumor oxygenation and blood flow, while 11 showed no response; 6 studies were technical failures. In one patient a metastatic node that had eluded orthodox investigation was visualized. A reduction in response was observed in the three patients studied postradiotherapy. CONCLUSION This method, which can be performed on a standard clinical MRI instrument, provides a noninvasive measurement of tumor response to oxygenation/blood flow modification. In principle, this should enable the clinician to optimize treatment protocols, such as carbogen breathing, for individual radiotherapy patients.

Improvement in human tumour oxygenation with carbogen of varying carbon dioxide concentrations

BACKGROUND AND PURPOSE Carbogen (95%O2, 5%CO2) is being used in clinical trials as a hypoxic radiosensitiser. Tolerance to carbogen can be a problem, this study compares tumour oxygenation during inhalation of hyperoxic gas containing either 2% or 5% CO2. MATERIALS AND METHODS Tumour pO2 was measured in 16 patients using the Eppendorf pO2 histograph. RESULTS After breathing gas containing either 5% or 2% CO2 an increase in median pO2 was measured in every tumour, the frequency of low pO2 values ( < or = 10 mmHg) fell from 47% to 29% in the 5% group and from 55% to 17% in the 2% group. CONCLUSIONS This study confirms that breathing 2% CO2 and 98% O2 is well tolerated and effective in increasing tumour oxygenation.

Accelerated radiotherapy, carbogen and nicotinamide (ARCON) in locally advanced head and neck cancer: a feasibility study

BACKGROUND AND PURPOSE ARCON (Accelerated Radiotherapy, CarbOgen, Nicotinamide) achieves a large therapeutic gain in rodents. A phase I/II study was therefore undertaken to determine its feasibility in patients with locally advanced head and neck cancer. MATERIALS AND METHODS The accelerated regime CHART was used in 35 patients given carbogen and/or nicotinamide with 11 small volume fractions. Eight patients received carbogen, 12 received nicotinamide and 15 were treated with ARCON. Treatment compliance, side-effects and acute mucositis were monitored in all cases. RESULTS All patients underwent CHART as intended. In the 23 patients receiving carbogen, two failed to complete treatment. Compliance with nicotinamide was much lower. Out of 25 patients, only 52% received 10-11 doses of the 80 mg/kg/day of the drug. The most common side-effect was nausea and vomiting, which responded to standard anti-emetics in almost half of the patients. Historical comparisons with the CHART head and neck trials indicate that there was no increase in the severity of acute mucositis in any of these patients. Although the observation period is not sufficiently long to be definitive (median 20 months) there is no evidence of an increase in late normal tissue reactions. CONCLUSIONS ARCON using CHART as the radiotherapy protocol is feasible in patients with advanced head and neck cancer. However, we are concerned about the low compliance rate in our patients, which is far lower than that reported elsewhere. The implications are discussed together with identifying strategies for increasing compliance.

Effect of carbogen breathing on tumour microregional blood flow in humans

BACKGROUND AND PURPOSE Carbogen is currently being re-evaluated as a radiosensitiser. It acts primarily by increasing tissue pO2, although there is evidence to suggest that enhanced tumour blood flow may also be a component of its action. MATERIALS AND METHODS Ten tumours in eight patients with advanced malignant disease were studied. Up to six microprobes, each with an estimated sampling volume of 10(-2) mm3, were inserted into the tumours. Ten min of baseline readings were taken prior to a 10 min carbogen (95% O2/5% CO2) breathing period, measurements were continued for a further 10 min. RESULTS The results show that in 34 microregions analysed no overall change in tumour perfusion was seen with carbogen breathing. Individual tumour analysis demonstrated variation in response between patients to carbogen-after 6 min of carbogen four tumours showed an increase in blood flow by more than 10% of the pre-breathing value, two a decrease and four no change. The magnitude of change was small, with only two tumours fluctuating by more than 25%. CONCLUSIONS These findings confirm the presence of transient fluctuations in microregional blood flow in human tumours but suggest that the radiosensitising action of carbogen lies primarily in its effect on increasing the oxygen capacity of blood. This supports the addition of agents such as nicotinamide with carbogen in order to overcome both diffusion and perfusion limited hypoxia.

Continuous hyperfractionated accelerated radiotherapy (CHART) in localized cancer of the esophagus

PURPOSE To assess the efficacy and toxicity of continuous hyperfractionated accelerated radiotherapy (CHART) in locoregional control compared with a historical group of patients treated with conventionally fractionated radical radiotherapy. METHODS AND MATERIALS Between 1985 and 1994, 54 patients with localized esophageal cancer were treated with CHART. Twenty-eight patients received CHART alone (54 Gy in 36 fractions over 12 consecutive days) and 15 were given intravenous mitomycin C and cisplatin on days 10 and 13, respectively. Eleven patients received 40.5 Gy in 27 fractions over 9 days, followed by a single high-dose-rate intraluminal brachytherapy insertion of 15 Gy at 1 cm. RESULTS Acute toxicity was well tolerated and dysphagia was improved in 35 patients (65%), with 28 (52%) eating a normal diet by week 12. This compares with an improvement in dysphagia score in 72% of the conventionally treated group. The median duration of relief of dysphagia was 7.8 months (range 0-41.4) in the CHART group compared with 5.5 months (range 0-48) in the controls. Strictures developed in 29 patients (61%) and 18 were confirmed on biopsy to be due to recurrent disease. Median survival was 12 months (range 0.5-112) in the CHART group and 15 months (range 3.6-56) in the control patients. CONCLUSION CHART is well tolerated and achieves a high rate of local control. Palliation in the short overall treatment time of esophageal cancer is an advantage in these patients whose median survival is only 12 months.

A feasibility study of continuous hyperfractionated accelerated radiotherapy (CHART) and brachytherapy in patients with early oral or oropharyngeal carcinomas

Overall time is important in the curative treatment of head and neck cancer (Dische, S., Saunders, M.I., Barrett, A., Harvey, A., Gibson, D., Parmar, M., 1997, Radiother. Oncol., 44:123-136). Results are presented on outcome and morbidity in ten patients with head and neck cancer treated with external beam irradiation (CHART protocol) and interstitial implantation, completing treatment in 12 days. Local control and overall survival at 5 years was 67%. Acute and late morbidity was acceptable giving scope for dose escalation.

422 How tolerable are the acute reactions of accelerated radiotherapy in head and neck cancer

It has been reported that if a radical dose is to be achieved with accelerated radiotherapy schedules, a gap in treatment is required. However, several groups have shown that effective total doses can be given without a gap. We have analysed the acute morbidity data in 99 patients with head and neck cancer treated with CHART between 1985 and 1990. All patients developed mucositis by week 3, with complete resolution in 60% and 82% by weeks 12 and 16 respectively. Symptoms of dysphagia mirrored these clinical findings, with 92% of patients developing moderate or severe dysphagia at week 3 which disappeared in 80% by week 12. Nasogastric feeding was required in 7 patients. Thirteen patients were hospitalised for between 1 and 4 weeks, for reasons relating to mucositis (6 patients) or suspected infection. Skin reactions were less of a problem. Maximum intensity of erythema was seen at week 3 but was severe in only 13%. Moist desquamation developed in 20% of patients between weeks 3 and 4 but in only 5% did it involve more than 25% of the treated field. In conclusion, the acute morbidity associated with this type of accelerated regimen is not unduly severe thus obviating the need for a gap in treatment.