Search

BACKGROUND: Only a small proportion of patients with non-small cell lung cancer (NSCLC) attending radiotherapy centres were suitable for inclusion in a randomised trial which compared continuous hyperfractionated accelerated radiotherapy (CHART) with conventional radical radiotherapy. As this was thought to be partly due to delays in the referral of patients to clinical oncologists, a prospective study was performed to determine the interval between first report of symptoms and first radiotherapy treatment in patients with NSCLC. METHODS: The time course from first symptom to treatment was determined in all patients with NSCLC attending 10 cancer centres for radiotherapy to a primary tumour in a three month period. RESULTS: Only 5% of 484 patients were suitable for the trial of radical radiotherapy. The principal causes for exclusion were poor general condition (37%), too large a tumour (27%), and extrathoracic metastases (19%). The median time from first symptom to diagnosis was 13 weeks, from first symptom to first treatment 19 weeks, and from diagnosis to first treatment five weeks. In a quarter of the patients these intervals were greater than 25,33 weeks, and nine weeks, respectively. CONCLUSION: The reason for these long intervals needs investigation since earlier diagnosis and more immediate referral for consideration of treatment might increase the number of patients with NSCLC suitable for radical radiotherapy.

This study investigated whether impaired respiratory function affected the response to radiotherapy. A prospective study was performed in which lung function, arterial oxygen and haemoglobin concentration were examined, before treatment with radical radiotherapy, in 141 patients with advanced non-small cell lung cancer and head and neck cancer. The findings were considered to reflect the physiological conditions present at the time of radiotherapy and these were related to acute normal tissue reactions and tumour control. Although 53% of the patients showed some impairment of lung function and 47% demonstrated a haemoglobin oxygen saturation below the normal range, oxygen partial pressure was below expected levels in fewer patients (27%) and total arterial oxygen content was below normal in only 12% of patients. No correlation was found between the tests performed and the severity of acute morbidity or with local tumour control. In the patients with carcinoma of the bronchus, there was a trend for incomplete tumour control to be associated with a lower haemoglobin level, but this did not reach statistical significance. In patients selected for curative radiotherapy, lung function would not appear to be an important factor influencing the response of normal tissues or tumour to irradiation.

In animal models carbogen (normobaric 95% oxygen, 5% carbon dioxide) provides significant enhancement of local tumor control with fractionated radiotherapy. This approach to radiosensitization has been evaluated in the treatment of patients with bladder carcinoma using radical radiotherapy.Sixty-one patients with locally advanced bladder carcinoma were treated using a Phase II trial delivering radiotherapy to the bladder (50-55 Grays in 20 daily fractions over 4 weeks) with inhalation of carbogen alone in 30 patients and the addition of oral nicotinamide (80 mg/kg) prior to radiotherapy with carbogen in 31 patients. The results from these 61 patients were compared with those from two earlier attempts at hypoxic sensitization: the second Medical Research Council (MRC) hyperbaric oxygen trial in patients with bladder carcinoma and a Phase III trial of misonidazole with radiotherapy in patients with bladder carcinoma performed at Mount Vernon Hospital.Although there was no difference between the hyperbaric oxygen and misonidazole trials, when compared with the two earlier series there was a large, statistically significant difference in favor of those patients receiving carbogen with or without nicotinamide for local control (P = 0.00001), progression free survival (P = 0.001), and overall survival (P = 0.04).Although the advantage for the carbogen group may be explained in part by changes in radiotherapy practice over the period of the three studies the improvement in local control is sufficiently great to support the hypothesis that hypoxia is important in modifying the control of bladder carcinoma using radiation therapy. Further evaluation of accelerated radiotherapy, carbogen, and nicotinamide in patients with bladder carcinoma is needed in a Phase III trial.

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.

Non-small cell lung cancer remains the commonest cause of cancer death in men, and the second in women. Disease often presents late, with inoperable tumour in the chest and a high chance of occult distant metastases. Despite radical treatment with radiotherapy and chemotherapy, it is estimated that over 80% of patients die with disease in their chest (Cox 1991) As control of the primary tumour is a pre-requisite for long term survival, radiation oncologists have concentrated on novel fractionation schedules as a method of altering the biological effect of the irradiation given, attempting to improve local tumour control with reduced long term side-effects.

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.

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.

A technique to deliver carbogen with high dose rate afterloading therapy to the oesophagus is described. Treatment is given using a standard high dose rate (HDR) afterloading catheter which is passed through the tumour-bearing area of the oesophagus within a nasogastric tube. In order to achieve a gas-tight seal, a standard "oxygen" mask used for delivery of carbogen is modified to incorporate the nasogastric tube allowing the treatment catheter to pass through the mask and be connected to the afterloading machine. The technique has proven to be feasible and well tolerated during treatment in four patients treated in this way. Severe acute radiation toxicity, possibly attributable to the carbogen, has been encountered in these patients receiving 1500 cGy at 1 cm via the HDR catheter after 4050 cGy in 27 fractions in 9 days using CHART external beam. Modifications to the radiation scheduling is recommended to enable carbogen to be incorporated in this way.

Direct comparison of bromodeoxyuridine (BrdUrd) and Ki-67 labelling indices was achieved by selecting similar areas from serial sections of human tumours. Fifteen patients were selected who had been administered BrdUrd in vivo and both proliferation markers were assessed by immunohistochemistry. The data show a good correlation between both BrdUrd LI and MIB-1 LI and Tpot (calculated using the flow cytometry derived duration of S phase) and MIB-1 LI. The contribution of BrdUrd LI to growth fraction varied as a function of proliferation characteristics. In tumours with a high LI, the number of DNA synthesizing cells represented half the growth fraction, whilst in tumours with lower LI's (10%) the ratio of DNA precursor labelled cells as a function of growth fraction fell to between 10% and 20%. Tpot showed a linear correlation with MIB-1/BrdUrd ratio with a slope approaching unity. It was apparent that both intra- and interpatient variation in proliferation index was greater for BrdUrd labelling than for MIB-1 expression.

Tumour cell hypoxia is a recognized cause of resistance to radiotherapy. Using clinically relevant dose-fractionation schedules in a mouse tumour model, the addition of carbogen and nicotinamide to overcome chronic and acute hypoxia results in a marked increase in radioresponsiveness with a lower degree of sensitization in normal tissue. Carbogen and nicotinamide were added to the palliative radiation treatment given to six patients with locally advanced breast cancer. The aim of the pilot study was to determine if patients tolerated the addition of carbogen and nicotinamide and to assess if there was any increase in radiosensitivity of the skin. Patients received 30 Gy prescribed to the intersection dose in six fractions over 17/18 days with full skin bolus to the tumour. All patients were given 6 g of nicotinamide orally 90 min before radiation treatment. Carbogen breathing was started 5 min prior to treatment and continued during it. Patients tolerated the treatment well, with vomiting in one patient being the only side effect that could be related to the nicotinamide, and this settled with an anti-emetic. No increase in skin reaction was noted with the addition of carbogen and nicotinamide, and good tumour regression was achieved.

EDITOR,--Heather Goodare and Richard Smith encourage patients to become involved in the establishment as well as the performance of clinical trials.1 In prospective randomised controlled clinical trials in malignant disease, patients are in general well prepared to cooperate and participate. However, they must first reach the treatment centre at a time when their condition is suitable for inclusion. The randomised controlled …

In a randomized controlled clinical trial of hyperbaric oxygen in the radiotherapy of carcinoma of the bladder a total of 241 cases were contributed by four radiotherapy centres in the United Kingdom. In this trial where in each centre identical radiotherapy was employed for both oxygen and air cases, no benefit was shown with the use of hyperbaric oxygen.

During recent years schemes of radiotherapy incorporating multiple treatments in one day have been introduced into the clinic. These can lead to a reduction in the overall duration of treatment (accelerated fractionation), an increase in the number of fractions in the same overall time (hyperfractionation), or a combination of both (Fowler, 1984). Two to five treatments have been given each day from Monday to Friday for 1, 2 or more weeks (Svoboda, 1978; Van der Schueren et al, 1985; Wang, 1985). It has usually been found necessary to reduce the individual dose increment from the conventional 1.8–2 Gy to between 1 Gy and 1.6 Gy but, even then, immediate reactions have prevented most workers from achieving a satisfactory total dose without interruption. Commonly, a split-course technique is employed with a rest period of 2–4 weeks to allow normal tissue reactions to settle before further radiotherapy is given. Retrospective comparisons in head and neck cancer have given improved results (Wang, 1985) but ra...

Misonidazole, a 2-nitroimidazole, is receiving extensive trial as a radiosensitizing drug in the treatment of patients with malignant disease. Drug sensitivity rashes have been observed and the collected cases from three centers are reported. Of a total of 380 patients there were five (1.3%) instances of definite rash and ten (2.6%) instances of observed rash. These figures are compared with the incidence of sensitivity rashes with other drugs in the nitroimidazole group.

In a randomized controlled clinical trial of hyperbaric oxygen in the radiotherapy of advanced carcinoma of the uterine cervix a total of 320 cases were contributed by four radiotherapy centres in the United Kingdom. The use of hyperbaric oxygen resulted in improved local control and survival. The benefit was greatest in patients under the age of 55 who presented with stage III disease. There was a slight increase in radiation morbidity but it seemed that the benefit of hyperbaric oxygen outweighed this increase in morbidity and that there was a true improvement in the therapeutic ratio.

A total of 62 patients with advanced tumours have now been treated by a fractionated course of radiotherapy, with misonidazole. The prime purpose of the administration of the drug to these patients was to determine safe dosage and suitable regimes for use in clinical radiotherapy. The reaction of normal tissues did not seem enhanced but there was an impression of increased tumour response.