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 approximate to 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.

AIMTo evaluate the feasibility, efficacy and toxicity of concurrent chemotherapy and continuous, hyperfractionated, accelerated radiotherapy weekend less (CHARTWEL) in the treatment of locally advanced, inoperable oesophageal cancer.METHODSA prospective study of 19 patients with histologically confirmed, locally advanced, inoperable carcinoma of the oesophagus. CHARTWEL was prescribed from day 1 to doses of 40.5 Gy (three patients), 42 Gy (five patients), 45 Gy (four patients), 46.5 Gy (three patients) and 49.5 Gy (four patients). Cisplatin 75 mg/m2 was administered on day 1 of radiotherapy, followed by 5-fluorouracil (5-FU) 1000 mg daily for 4 days.RESULTSAll patients completed radiotherapy, with two requiring modification of their chemotherapy dose. Acute toxicity was acceptable, with no interruptions to treatment. The median dysphagia free time was 9.6 months with 38% of patients being dysphagia free at 42 months. The median time to locoregional relapse was 13.2 months with 50% being free at 1 year and 35% at 3.5 years. There was a trend towards greater control when the higher doses (45-49.5 Gy) were compared with the lower doses (40.5-42 Gy), P = 0.07. The median survival time was 10.7 months with 1- and 2-year survival rates of 50 and 26%, respectively. Strictures developed in seven out of 18 patients (38%), but five were found on biopsy to be due to recurrent disease. There was no other long-term toxicity and no treatment-related death occurred.CONCLUSIONSCHARTWEL with concomitant cisplatin/5-FU chemotherapy is a feasible treatment option in these patients. It is well tolerated, achieves a high rate of local control and effectively palliates the symptoms of dysphagia, all with relatively rapid resolution of treatment-related toxicity. The results warrant continued dose escalation to 51 Gy.

PURPOSE a radiation-dose-escalation study was undertaken to assess the therapeutic benefit of combining accelerated hyperfractionated radiotherapy (RT) with neo-adjuvant chemotherapy (CT) in non-small-cell lung cancer (NSCLC). MATERIALS AND METHODS One hundred and thirteen patients with locally advanced NSCLC were entered into a phase II trial of CHARTWEL (CHART Week-End-Less) 54 Gy or 60 Gy with or without three cycles of CT. Acute oesophageal reactions and analgesia were scored for up to 8 weeks after the start of RT. Pneumonitis, lung fibrosis, spinal cord and oesophageal strictures, were assessed using clinical and radiological criteria from 3 months onwards and throughout the study. Haematological and gastrointestinal toxicity was monitored in those patients undergoing CT. Endpoints for treatment outcome were overall survival, disease-free survival and loco-regional control. RESULTS Chemotherapy enhanced the incidence and duration of acute dysphagia,but the increase was transient. Healing occurred in all cases and there has been no evidence of long-term oesophageal complications. Clinically, almost 25% of those receiving CT+RT had Grade 2 pneumonitis, higher than seen with RT alone. However, the 1 patient with severe Grade 3 pneumonitis was in the RT 60 Gy alone group. An incidence of 17% Grade 2 pulmonary fibrosis at 2 years was seen with CT, slightly lower than with RT alone. To date, there is no evidence of Grade 3 lung fibrosis. There was a higher scoring of lung damage with the radiological endpoint, which gave no indication that CT increased pulmonary toxicity over that of RT alone. Loco-regional control at 2 years was 37% and 55% for CHARTWEL 54 Gy and 60 Gy alone compared with 72% in those treated with 60 Gy and neo-adjuvant CT However, this did not translate into a survival advantage. CONCLUSIONS This study of CHARTWEL combined with induction chemotherapy, has shown that the strategy is feasible and that a possible therapeutic benefit may be obtained by the addition of CT. Although neo-adjuvant treatment increased acute mucosal reactions and slight-to-moderate pneumonitis seen with CHARTWEL 60 Gy, the clinical management and quality of life of these patients is similar to those treated with radiotherapy alone.

An MRI method is described for demonstrating improved oxygenation of human tumors and normal tissues during carbogen inhalation (95% O-2, 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. (C) 2001 Wiley-Liss, Inc.

Purpose: To test the hypothesis that there is a link between plasma glutathione (GSH) or other antioxidants (uric acid. ascorbate) and the severity of radiation mucositis following radiation treatment of tumors of the head and neck.Patients and Methods: Patients with carcinomas of the head-and-neck region were treated with the continuous hyperfractionated accelerated radiotherapy (CHART) regimen (54 Gy in 36 fractions over 12 days). Samples of blood plasma were analyzed for GSH, cysteine, urate, and ascorbate by high-pressure liquid chromatography. Patients were graded for dysphagia and requirement for analgesics. The areas under the curves of scores over 2-6 weeks following treatment were computed, and Spearman's rank-correlation coefficient was used to test for an association between plasma GSH levels (or those of other antioxidants) and mucositis.Results: The pretreatment plasma GSH level in 18 patients scored in the study was 1.0 +/- 0.7 muM. Analysis of these and the dysphagia scores produced a correlation coefficient of 0.22 (confidence interval -0.28, 0.61; p = 0.39). No correlation was seen between mucositis severity and other measures of plasma antioxidants: cysteine (7.6 +/- 1.7 muM), cysteine + GSH (8.6 +/- 1.9 muM), uric acid (317 +/- 86 muM), ascorbate (29 +/- 20 muM), or whole-blood GSH concentrations (1,010 +/- 239 muM).Conclusion: The measurements of approximately micromolar levels of plasma GSH, or about 10 muM cysteine + GSH (almost all of the total nonprotein thiols), are consistent with most other published data for either healthy adults or cancer patients; however, the values reported in an earlier study, suggesting a link between GSH and mucositis, are much higher. The hypothesis of a possible link between radiation mucositis and plasma-free (nonprotein) thiols was not supported. (C) 2001 Elsevier Science Inc.

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.

Capnometer measurements during 46 evaluable treatments in which patients were administered carbogen (95% O2, 5% CO2) have demonstrated that the mean inspired carbon dioxide level was 3.1% (range 0-4.7) and the mean inspired oxygen concentration was 70.6% (range 26.4-94). The explanation for this observation is leakage of air into the breathing system during radiotherapy.

This pilot study investigated the feasibility, toxicity and effect of continuous, hyperfractionated, accelerated radiotherapy (CHART) in 19 patients with adenocarcinoma of the rectum who were treated at Mount Vernon Hospital between April 1992 and April 1994. A total dose of 54 Gy was given in 36 fractions over 12 consecutive days; three fractions of 1.5 Gy were employed each day with an interfraction interval of 6 hours. Of these 19 patients, 13 had local pelvic recurrence from rectal carcinoma, four had a primary rectal carcinoma (which was unsuitable for abdominoperineal resection because of patient frailty), and two had large, fixed, unresectable tumours and were given radiotherapy preoperatively to a lower dose of 42 Gy in 28 fractions over 10 days to facilitate surgery. However, none of the 19 patients subsequently underwent surgical resection. Treatment compliance with radiotherapy was 95%. Acute bowel toxicity was assessed by means of a daily bowel chart for 6 weeks and then at 8, 12 and 26 weeks after the completion of radiotherapy. Patients were subsequently scored using the World Health Organization (WHO) grading system. No toxic deaths were observed in this study. There were five grade 3 and one grade 4 toxicities (WHO scale) observed in six patients. There has been minimal acute bladder toxicity in two patients and skin reactions have been surprisingly minimal in all but three patients. Small bowel obstruction and late bowel damage, possibly attributable to radiotherapy, occurred in three patients. Complete pain relief was achieved in recurrent rectal cancer in 100% of patients, at a median of 15 days since commencing radiotherapy (range 7-63 days), and has been maintained for mean and median durations of 19 and 18 months respectively (range 1.5-45 months). Five patients have had a recurrence of pain at 3, 4, 8, 9 and 18 months respectively. All four patients with primary rectal adenocarcinoma achieved a complete response, which has been sustained for 4 months (until death), 54 and 57 months, although one patient relapsed locally at 8 months. In summary, CHART appears to be a feasible treatment for pelvic tumours with regard to toxicity. Patients with pain from a locoregional recurrence achieved rapid complete pain relief, which was sustained for many months.

Results from the multicentre randomized trial of CHART (continuous, hyperfractionated, accelerated radiotherapy) in non-small-cell lung cancer (NSCLC) showed a significant increase in survival (P=0.004) compared with conventional radiotherapy and a therapeutic benefit relative to late radiation-induced morbidity. However, 60% of patients died because of failure to control locoregional disease. These findings have stimulated interest in assessing the feasibility of dose escalation using a modified CHART schedule. Acute and late morbidity with a CHARTWEL (CHART WeekEnd Less) schedule of 54 Gy in 16 days was compared with that observed with 60 Gy in 18 days in patients with locally advanced NSCLC. The incidence and severity of dysphagia and of analgesia were scored using a semiquantitative clinical scale. Late radiation-induced morbidity, namely pulmonary, spinal cord and oesophageal strictures, were monitored using clinical and/or radiological criteria. Acute dysphagia and the analgesia required to control the symptoms were more severe and lasted longer in patients treated with CHARTWEL 60 Gy (P< or = 0.02). However, at 12 weeks, oesophagitis was similar to that seen with 54 Gy and did not lead to consequential damage. Early radiation pneumonitis was not increased but, after 6 months, there was a higher incidence of mild pulmonary toxicity compared with CHARTWEL 54 Gy. No cases of radiation myelitis, oesophageal strictures or of grade 2 or 3 lung morbidity have been encountered. CHARTWEL 60 Gy resulted in an enhancement of oesophagitis and grade 1 lung toxicity compared with CHARTWEL 54 Gy. These were of no clinical significance, but may be important if CHARTWEL is used with concomitant chemotherapy. These results provide a basis for further dose escalation or the introduction of concurrent chemotherapy.

Carbogen and nicotinamide have been evaluated in a phase II 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.

The effect of inhibiting gastric acid secretion on nicotinamide pharmacokinetics was studied in five volunteers with the intent of reducing the large variations observed previously in the time to and magnitude of peak plasma concentrations. Plasma levels were determined using a standard high-performance liquid chromatography (HPLC) method after an oral dose of 3 g of nicotinamide either alone or preceded by pretreatment with omeprazole. Suppression of gastric acid production had no significant effect on the rate of uptake or on the peak levels achieved. To bypass gastric acidity, the rectal route was also assessed using a suppository in four volunteers and one patient undergoing radiotherapy. Absorption was slow and variable and much lower plasma levels were observed than after oral dosing. Thus, no improvement in the pharmacokinetics of nicotinamide was observed using either of these two approaches. Parallel estimations were made using a novel and non-invasive method for monitoring nicotinamide pharmacokinetics in saliva. A large and variable fraction of the total amount of nicotinamide-related material in saliva was found to be nicotinic acid, a metabolite not normally found in human plasma. This conversion was inhibited by the use of a chlorhexidine mouthwash, indicating that the oral flora was responsible for its production. The time to peak levels of nicotinamide or of nicotinamide plus nicotinic acid in saliva correlated well with that in plasma. However, peak concentrations for nicotinamide alone were significantly lower than in plasma, and very variable, whereas for nicotinamide plus nicotinic acid saliva levels were 20-30% higher, but more consistent. Although there are some practical difficulties in quantitatively handling saliva, the method is very useful for monitoring nicotinamide pharmacokinetics and for assessment of compliance with nicotinamide treatment.