Biomedical subjects

M I Saunders

Publications and source records attributed to M I Saunders.

At least 37 records · Page 2Linked to original sources

PubMed1999

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.

Administration, Inhalation↗

PubMed1999

Inspired and expired gas concentrations in man during carbogen breathing.

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.

Capnography↗

PubMed1999

Carcinoma of the cervix and the use of hyperbaric oxygen with radiotherapy: a report of a randomised controlled trial.

BACKGROUND AND PURPOSE: A randomised controlled trial of hyperbaric oxygen in the radiotherapy of Stage IIb and III carcinoma of cervix was performed between 1971 and 1980. Apart from an abstract giving an interim report in 1977, results have not been published. MATERIAL AND METHODS: In a four arm study, 335 patients were randomised to treatment in 10 or 28 fractions, in hyperbaric oxygen or in air. Data is available concerning 327 cases and this has been analysed. RESULTS: There was no advantage in tumour control shown with the use of hyperbaric oxygen. There was evidence for an increase in late radiation morbidity when treatment was given in hyperbaric oxygen rather than in air and when, using 10 fractions, a total dose of 45 rather than 40 Gy was achieved. For late intestinal morbidity, the fractionation sensitivity (alpha/beta ratio) was calculated to be 4.3 Gy and the steepness of the dose response curve (gamma50) to be 2.6. CONCLUSIONS: Hyperbaric oxygen gave no benefit in the treatment of patients with stage IIb and III carcinoma of the cervix treated with radiotherapy using two fractionation regimes. Important data regarding late radiation morbidity has been revealed.

Adult↗

PubMed1999

Repair halftimes estimated from observations of treatment-related morbidity after CHART or conventional radiotherapy in head and neck cancer.

BACKGROUND AND PURPOSE: The CHART (Continuous Hyperfractionated Accelerated Radiotherapy) head and neck cancer fractionation schedule delivered 54 Gy in 36 fractions on 12 consecutive days and this was compared in a randomised controlled trial with conventional fractionation delivering 66 Gy in 33 fractions over 6-7 weeks. Patients receiving CHART experienced statistically significantly less treatment-related morbidity after 6 months than patients receiving conventional fractionation. However, this improved tolerance was much less than anticipated from existing knowledge of dose-fractionation effects on late-responding normal tissues. Here, the experience from the CHART study is analysed and repair halftimes for three types of late treatment-related morbidity of human tissues are estimated. PATIENTS AND METHODS: The CHART trial was open for patient accrual from March 1990 to April 1995 and a total of 918 patients in 11 participating centres were randomised. All patients were followed at regular intervals for a minimum of 5 years or until the time of death. At each follow-up, a number of treatment-related morbidity items were evaluated and scored prospectively. Data for three late endpoints are analysed here: laryngeal oedema, skin telangiectasia and subcutaneous fibrosis. Differences in the incidence of these endpoints in the two trial arms were quantified by means of the ratio of hazard rates in a Cox proportional hazards model. Monte Carlo sampling was performed from distributions of fractionation sensitivity (quantified by the alpha/beta-ratio) and steepness of the dose-response curve (quantified by the normalised dose-response gradient, gamma50) with means and standard deviations derived from the literature. Each pair of values were used to convert a Monte Carlo sampled estimate of the difference in biological effect into an estimate of the repair halftime. From the distribution of 1000 Monte Carlo samples, the mean repair halftime and its 95% confidence interval were estimated. RESULTS: The estimated repair halftimes, with 95% confidence intervals in parentheses, were 4.9 h (3.2, 6.4) for laryngeal oedema, 3.8 h (2.5, 4.6) for skin telangiectasia and 4.4 h (3.8, 4.9) for subcutaneous fibrosis. Calculations show that these repair halftimes are consistent with the observations from two published randomised controlled trials of altered fractionation in head and neck cancer, the EORTC 22791 and 22851 trials. CONCLUSIONS: These long repair halftimes for late effects in human normal tissues have to be considered in order to gain the full benefit from fractionation schedules employing multiple fractions per day.

Carcinoma, Squamous Cell↗

PubMed1999

Anti-tumour promoter activity in Malaysian ginger rhizobia used in traditional medicine.

Zingiberaceae rhizomes commonly used in the Malaysian traditional medicine were screened for anti-tumour promoter activity using the short-term assay of inhibition of 12-O-tetradecanoyl phorbol-13-acetate (TPA)-induced Epstein-Barr virus early antigen (EBV-EA) in Raji cells. The inhibition of TPA-induced EBV-EA was detected using the indirect immunofluorescence assay (IFA) and Western blot technique. The indirect IFA detected the expression/inhibition of EBV-EA-D (diffused EA antigen), whereas the Western blot technique detected the expression/inhibition of both EBV-EA-D and EA-R (restricted EA antigen). Seven rhizomes were found to possess inhibitory activity towards EBV activation, induced by TPA; they are: Curcuma domestica, C. xanthorrhiza, Kaempferia galanga, Zingiber cassumunar, Z. officinale, Z. officinale (red variety), and Z. zerumbet. A cytotoxicity assay was carried out to determine the toxicity of the Zingiberaceae rhizome extracts. The rhizome extracts that exhibited EBV activation inhibitory activity had no cytotoxicity effect in Raji cells. Therefore, the present study shows that several Zingiberaceae species used in Malaysian traditional medicine contain naturally occurring non-toxic compounds that inhibit the EBV activation, which, if further investigated, could contribute in the development of cancer prevention methods at the tumour-promoting stage.

Anticarcinogenic Agents↗

PubMed1999

A pilot study of continuous, hyperfractionated, accelerated radiotherapy in rectal adenocarcinoma.

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.

Adenocarcinoma↗

PubMed1999

The CHART regimen and morbidity.

In 1984, when the CHART regime was devised, it was predicted that acute reactions in skin and mucosae would be more severe but that there would be a considerable reduction of late effects in normal tissues. The findings from the pilot study conducted from 1985 to 1990 and from the randomized trials, which entered cases from 1990 to 1995, are reviewed. With CHART, it was found that acute mucosal reactions were more severe but tolerable and recoverable. Unexpectedly, acute skin reactions were reduced rather than increased. Late reactions in the central nervous system have led to a dose restriction of 40 Gy. Effects in other normal tissues were significantly reduced but the sparing effect was less than that predicted. This can perhaps be explained by a half-time of repair of sublethal injury in human tissues in excess of 4 h.

Dose Fractionation, Radiation↗

PubMed1999

Dynamic contrast enhanced magnetic resonance scanning as a predictor of response to accelerated radiotherapy for advanced head and neck cancer.

Tumour perfusion has been assessed in patients with advanced head and neck cancer using dynamic contrast enhanced MRI prior to and at completion of accelerated radiotherapy, and related to local tumour control. Sequential MRI scans, at 3 s intervals after intravenous injection of gadolinium using a dynamic scan sequence through a tumour region of interest (ROI), were performed in 13 patients with advanced head and neck cancer before and on completion of radiotherapy. The scans have been analysed in terms of maximum tumour enhancement (E), slope of the enhancement versus time curve and the time taken to reach maximum tumour enhancement (Tmax), and these parameters related to tumour outcome after radiotherapy. Local tumour control was related to the value of E on a post-radiotherapy scan and the difference in Tmax between a pre- and post-radiotherapy scan. Durable local control was seen in those tumours with a post-radiotherapy value for E of less than 8 and a mean fall in Tmax of 27.3 s. These results imply that tumours with diminished tumour perfusion at the end of radiotherapy are those most sensitive to treatment and that those tumours which show greater tumour enhancement after accelerated radiotherapy are likely to fail locally. This may reflect the persistence of viable perfused tumour at completion of radiotherapy.

Contrast Media↗

PubMed1999

Head and neck cancer: altered fractionation schedules.

Local control is paramount in the treatment of localized advanced head and neck cancer. Standard radiotherapy cures a high percentage of early tumors--more than 80% of the early laryngeal tumors--but fewer of the advanced tumors. Attempts have therefore been made to improve the therapeutic ratio by: A) hyperfractionation: reducing the dose per fraction to reduce late morbidity; the total dose is then elevated in an attempt to improve local tumor control with equal morbidity, and B) acceleration: reducing the overall treatment time to overcome repopulation during a protracted course of radiotherapy. The total dose and dose per fraction have been reduced in the accelerated arm in some trials, while in others the total dose has been maintained. Both these strategies have been tested in multicenter randomized controlled trials, but neither have become part of routine clinical practice. The biological parameters determining local tumor control and normal tissue effects are being studied at Mount Vernon by an analysis of selected randomized controlled trials, with the aim of designing new schedules of radiotherapy for future studies.

Carcinoma, Squamous Cell↗

PubMed1998

Experience with dose escalation using CHARTWEL (continuous hyperfractionated accelerated radiotherapy weekend less) in non-small-cell lung cancer.

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.

Aged↗

PubMed1997

Human tumor blood flow is enhanced by nicotinamide and carbogen breathing.

Perfusion insufficiency and the resultant hypoxia are recognized as important mechanisms of resistance to anticancer therapy. Modification of the tumor microenvironment to increase perfusion and oxygenation of tumors may improve on the efficacy of these treatments. Using laser Doppler probes to measure microregional RBC flux, this study examines the influence of nicotinamide and carbogen on human tumor perfusion. Ten patients with advanced cancers were studied. Nicotinamide (80 mg/kg) was given p.o., and 60 min later, up to six probes were inserted into the tumor. Readings were taken for 1 h, followed by 10 min of carbogen breathing and 10 additional min of breathing room air. Results were compared with those from a similar group of eight control patients who were not given nicotinamide, but who breathed carbogen. In 44 microregions analyzed, 33 (73%) showed perfusion fluctuations of 50% or more, and 20 (44%) by 100% or more. This compared with the control group in whom 62% and 27% of microregions varied by 50% or more and 100% or more, respectively. Perfusion increases outweighed decreases by 30% with nicotinamide and 20% in the controls. On breathing carbogen, patients pretreated with nicotinamide showed an increase in tumor perfusion of 17% at 5 min and 22% at 10 min, compared with only 0% and 1% in the control group. Pretreatment with nicotinamide made little difference to the random blood flow fluctuations seen in controls. However, when carbogen was introduced, tumor perfusion increased compared with the control group. This may have important therapeutic implications by improving response to treatment and allowing better delivery of systemically administered agents.

Administration, Inhalation↗

PubMed1997

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.

Administration, Inhalation↗

PubMed1997

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.

Adult↗

PubMed1997

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.

Administration, Oral↗

PubMed1997

Carbogen and nicotinamide in the treatment of bladder cancer with radical radiotherapy.

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.

Aged↗

PubMed1997

Fractionation in radiotherapy: a view from the clinic.

A century of the evolution of the fractionation of radiotherapy has brought clinical oncologists to the testing of protocols in randomized controlled clinical trials. The British Institute of Radiology's pioneering trials, together with more recent studies, are described and future developments suggested.

Dose Fractionation, Radiation↗

PubMed1996

Microregional fluctuations in perfusion within human tumours detected using laser Doppler flowmetry.

PURPOSE: Transient fluctations in erythrocyte flux consistent with perfusion driven hypoxia have been previously reported using experimental tumour models. The present study was designed to establish whether such changes are a common feature of human tumours. METHODS AND MATERIALS: A multi-channel laser Doppler system was used to monitor microregional changes in flow in human tumours. Eight individual tumours were investigated, two primary and one locally recurrent breast carcinoma, two metastatic skin deposits and three metastatic lymph nodes. Six custom designed microprobes (diameter of 300 microns), each monitoring a nominal sampling volume of approximately 10(-2) mm3 were inserted into the tumour and perfusion monitored over a period of 60 min. RESULTS: The results show that in 54% of the regions monitored there was a change in microregional blood flow by a factor of 1.5 or more. Over the whole 60-min period, 19% of the changes were reversed, with a time course of 4-44 min. CONCLUSIONS: This finding demonstrates that microregional fluctuations in perfusion occur frequently in human tumours. Furthermore, the observation that 19% of the changes were reversed implies that at least some of the cells are subject to transient acute hypoxia.

Aged↗

PubMed1996

The dental problems of patients with head and neck cancer treated with CHART.

Between 1985 and 1990, 99 head and neck cancer patients were treated at Mount Vernon Centre for Cancer Treatment in a CHART pilot study. The aims of this retrospective review were to obtain baseline data for this population on their pretreatment dental status and to determine the extent to which our conservative policy of teeth preservation is being realised. This is of particular interest because of the believed sparing of late normal tissue effects by CHART compared with conventional fractionation. Prior to treatment, 40% of patients were edentulous, and prophylactic dental clearance was avoided in 59% of the remaining (dentate) patients. Following radiotherapy, only 21% of dentate patients subsequently lost all their remaining teeth. The proportion of patients with full or partial upper dentures increased from 61% pretreatment to 76% post-treatment; the corresponding increase in lower dentures was 46% to 66%. However, actual usage of dentures decreased somewhat. There was only one documented case of (minor) osteo-radionecrosis of the mandible which resolved with conservative care. The greater use in our patients of prophylactic measures, in particular, chlorhexidine and fluoride mouthwashes seemed indicated.

Adult↗