Salvage surgery following irradiation with different fractionation regimes in the treatment of carcinoma of the laryngo pharynx: experience gained from a British Institute of Radiology study.

The 10-year follow-up of patients in a clinical trial involving the comparison of treatment by three fractions per week versus five fractions per week in radiotherapy of squamous carcinoma of the larynx and hypopharynx has now been completed. The trial involved an intake of 734 patients between 1966 and 1975. No statistically significant differences have been found between the two trial arms in terms of overall survival, age corrected survival, local recurrence, laryngectomy-free rates or effects on the normal tissues. Local recurrence was found in 320 of the 713 evaluable patients (45 per cent). Salvage laryngectomy was performed in 151 of the 320 patients with recurrence (47 per cent). Survival at 10 years for all node negative patients was 50 per cent in those patients without primary recurrence, compared with 40 per cent in those undergoing salvage laryngectomy.

Normal tissue reactions in the British Institute of Radiology Study of 3 fractions per week versus 5 fractions per week in the treatment of carcinoma of the laryngo-pharynx by radiotherapy.

The radiobiological data obtained from a multicentre clinical trial of the British Institute of Radiology, which compared the treatment of carcinoma of the laryngo-pharynx by 3 fractions per week (3F/wk) with 5 fractions per week (5F/wk) radiotherapy, have been studied. The trial involved an intake of 734 patients between 1966 and 1975. The number of fractions, overall treatment time and total doses used by different treatment centres ranges from 9 to 40 fractions, 18 to 70 days and 3880 to 7800 cGy, respectively. An 11-13% reduction in the total radiation dose was applied for treatments with 3F/wk as compared with 5F/wk in centres treating over 6 weeks and 3 weeks, respectively. All patients were followed for 10 years from the start of treatment. Different types of early and late normal-tissue reactions were investigated, ranging from a low percentage incidence of perichondritis to 95% for slight early reactions. Greater than 80% of the late normal-tissue reactions seen were observed within the first year after the start of treatment, and 96% were observed within the first 5 years. There was no statistically significant difference in the normal-tissue event-free rates between the 3F/wk and 5F/wk treatment groups. This finding did not differ when different major treatment centres were studied separately. For a number of end-points, alpha/beta ratios and N- and T-exponents of a modified nominal standard dose (NSD) formula have been calculated.

The predictive value of histological classification into degrees of differentiation of squamous cell carcinoma of the larynx and hypopharynx compared with the survival of patients.

In the course of running two clinical trials between 1966 and 1985, data became available for 1315 patients, 713 in the first trial and 602 patients in the second trial, which has allowed comparison between histological findings in laryngeal and hypopharyngeal carcinoma, the observed survival and the tumour-free rates for these patients who were followed for up to 10 years. Extensive histopathology reviews have revealed over 98% agreement on tumour cell type between the initial report and that of the reviewer. Highly significant differences have been found for squamous cell carcinoma between the observed survival and the tumour-free rates for patients with well-differentiated and with anaplastic lesions. There was a statistically significant greater proportion of patients with well-differentiated tumours at larynx sites and in stage 1 when compared with patients with anaplastic tumours, but even when this was taken into account, multivariate analyses showed that tumour grading still made an independent significant contribution to the prediction of prognosis. For squamous cell carcinoma only very simple and rapidly assessed histopathological features need to be identified to classify tumours into the two grades employed in this study. The analyses have confirmed the prognostic significance of tumour grading in squamous cell carcinoma in the larynx and hypopharynx.

Final report on the second British Institute of Radiology fractionation study: short versus long overall treatment times for radiotherapy of carcinoma of the laryngo-pharynx.

The second British Institute of Radiology trial of dose fractionation in radiotherapy compared two groups of prospectively randomized patients with squamous carcinoma of the laryngo-pharynx; one group was treated in a short (less than or equal to 4 weeks) and the other in a long (greater than 4 weeks) overall time. Treatment in any one centre could be given, with no planned gap in the course of treatment, either as a conventional, daily (5 fractions per week regime) or as 3 fractions per week. A total of 611 patients were allocated to treatment, of whom nine have had to be excluded from the analysis for a lack of information. Patients were admitted to the trial from January 1976 to December 1985 and were followed up for a maximum of 10 years and a minimum of 3 years. A reduction in total dose was made for use in the short compared with the long treatment regime. This reduction in total dose varied between 18% and 22% depending on whether 5 fractions or 3 fractions per week regimes were used. Overall, no statistically significant differences have been found between the two arms of the trial. The patients treated with 5 fractions per week in a short overall treatment time showed fewer late normal tissue effects. An analysis based on stratification by age, stage and anatomical site gave a relative risk (short/long overall treatment time) for deaths of 1.23 with a 95% confidence interval from 0.96 to 1.59. Analyses stratified for stage and site gave relative risks with 95% confidence intervals of 1 x 10 (0.84-1.44) for local recurrences/tumour persistence, and 1.01 (0.70-1.45) for laryngectomies.

The relative biological effectiveness of fractionated doses of fast neutrons (42 MeVd----Be) for normal tissues in the pig. II. Late effects on cutaneous and subcutaneous tissues.

The late effects of irradiation with single and fractionated doses of X rays (250 kV) and fast neutrons (42 MeVd----Bc), on the cutaneous and subcutaneous tissues of the pig, have been evaluated from measurements of changes in relative field length. These were determined at intervals of 26-104 weeks after irradiation. For fractionated irradiation with X rays the average fractions exponent, N, obtained from a log-log plot of iso-effect dose (ED50) against fraction number was 0.41. This was independent of the period of assessment, with no significant indication of a time factor. However, the exponent N did vary with the level of effect and was in the range 0.33-0.51. It was greatest for a greater than or equal to 10% reduction in relative field length. Assuming the validity of the linear quadratic model of cell survival, the alpha/beta ratio was 1.95 Gy. However, this model fitted the data less well for the least severe levels of damage, and for these the alpha/beta ratios were not significantly different from zero. Irradiation with fast neutrons showed a small effect of fractionation for doses given in greater than or equal to 6 fractions compared with a single dose. There was no significant increase in iso-effect dose when the dose was given in 30 fractions compared with 6 fractions. The relative biological effectiveness for late cutaneous and subcutaneous damage for the energy of fast neutrons used did not vary with the period of assessment, i.e. 26-52 weeks compared with 65-104 weeks, and was not significantly different from that previously obtained for ischaemic dermal necrosis, seen after higher doses, at 12-20 weeks after irradiation.

Recruitment, follow-up and analysis times in clinical trials of cancer treatment: a case study.

A study has been made of the way in which the number of events available for analysis in a clinical trial was dependent on the recruitment period, the maximum follow-up time on individual patients and the length of time between the start of the trial and its analysis. The events considered were deaths, local recurrences and late radiation effects on normal tissue in patients treated for cancer of the laryngo-pharynx by two different fractionation regimes. The relationship is demonstrated between the number of events and the 95% confidence intervals that can be placed on differences between results in the two arms of the trial. It was found, in this particular trial, that no significant improvement in precision was gained by following up patients beyond 5 years or carrying out the analysis later than 2 years after the end of recruitment. The results are discussed in the context of the initial design of clinical trials, particularly those in which the aim is to test therapeutic equivalence.

The predictive value of tumor classification compared with results of the British Institute of Radiology fractionation trial in the treatment of laryngopharyngeal carcinoma.

Data from a clinical trial involving 734 patients have shown the value and the deficiencies of the current Union Internationale Contre le Cancer's tumor, node, and metastasis classification system for prognostic purposes. The tumor-category classification provides a good discriminant for both nodal involvement and survival; however, the previous node classification system only discriminated between node-negative and node-positive patients, as nodal fixity was not found to be a discriminator. The current anatomical site classification is ambiguous for some laryngeal and pharyngeal subsites, and modifications to the present system based on prognostic values are proposed. A difference in patient age between tumor categories has been shown, and various differences in incidence and survival data for the sexes have been demonstrated. Differences in observed and expected survival rates are related to continued late deaths from tumor. Multivariate analyses have shown that stage grouping is the most powerful prognostic discriminator, followed by anatomical site and age.

Final report of the general clinical results of the British Institute of Radiology fractionation study of 3F/wk versus 5F/wk in radiotherapy of carcinoma of the laryngo-pharynx.

The 10 year follow-up of a clinical trial involving the comparison of 3F/wk versus 5F/wk in radiotherapy of squamous cell carcinoma of the larynx and hypopharynx has now been completed. The trial involved an intake of 734 patients between 1966 and 1975. The classification of all patients has been revised to conform with the latest TNM publication. A reduction in total dose was made for 3F/wk compared with 5F/wk. This varied between 13% and 11% in centres treating over 3 weeks and 6 weeks, respectively. No statistically significant differences have been found between the two arms (3F/wk versus 5F/wk) of the trial in any of the main group analyses. A number of sub-group analyses relating to survival, tumour-free and laryngectomy-free rates and to the comparison of acute or late normal-tissue radiation damage have also been performed. No differences have been found that could be considered to be statistically significant in relation to the particular sub-group. Previous interim reports suggested minor differences in sub-group analyses between the 3F/wk and 5F/wk regimes in this trial; these have diminished now that the full follow-up data are available. This trial has provided evidence on which clinicians may base their choice between either a 3F/wk fractionation regime or a conventional 5F/wk treatment protocol in the treatment of carcinoma of the laryngo-pharynx.

Dosimetric intercomparison in the British Institute of Radiology fractionation study of 3F/week versus 5F/week in radiotherapy of laryngo-pharynx cancer.

A dose intercomparison was carried out by the National Physical Laboratory between the seven radiotherapy centres which contributed the largest number of patients to the British Institute of Radiology fractionation study of three fractions per week versus five fractions per week in clinical cancer treatment. Six of the centres showed remarkable agreement within the acceptable limits of error of the measurements. In one centre there appeared to be a physical dose discrepancy of 2.8% which was materially less than could be detected clinically.

First interim progress report on the second British Institute of Radiology Fractionation Study: short versus long overall treatment times for radiotherapy of carcinoma of the laryngopharynx.

Preliminary data from a second British Institute of Radiology Fractionation Trial comparing short (less than or equal to 4 weeks) and long (greater than 4 weeks) overall treatment times are reported. The intake of patients ran from January, 1975 to December, 1985 when 611 patients with carcinoma of the laryngo-pharynx were registered in this prospective, randomized, multicentre clinical trial. No significant differences have, so far, been demonstrated between the two arms of the trial with respect to observed survival rates, tumour-free or laryngectomy-free rates. Further long-term follow-up is continuing.

The combination of radiotherapy and surgery in the treatment of carcinoma of the uterine cervix.

In the Department of Radiotherapy and Oncology at Oxford, 1303 patients were registered between 1950 and 1975 with a diagnosis of carcinoma of the uterus; from these, 883 cases of carcinoma of the uterine cervix could be identified with certainty. Each patient's full clinical record was established from multiple hospital notes, operating theatre records, histopathological report files and so on. A uniform classification, based on the TNM system, was used for all patients. A data file, suitable for computer analysis, was established which contained all the available data. Analysis revealed that all patients could be divided into two distinct groups that had been prospectively determined and that the allocation achieved was random. The results, by various methods of analysis, show consistently that a policy of radical radiotherapy combined with radical surgery gave an increased survival rate, and a decreased mortality rate from cancer when compared with a treatment policy of only radical radiotherapy. During the 25 years being reviewed there was a progressive increase in the number of young patients with cancer of the uterine cervix in the early stages of disease at presentation and in the survival of patients with the early stages of invasive cancer.

Fractionation in radiotherapy (review).

The methods by which radiation treatment has been administered since the original discoveries concerning the properties of ionising radiation are reviewed on a historical basis. The criteria, together with their limitations, that have influenced the empirical approach to fractionation in radiotherapy are identified and critically assessed. The necessity for classifying fractionation into component parts, so as to avoid confusion, such as time, dose and fractions factors is stressed, as is the correct evaluation of the complex biological consequences of the physical events. The different mechanisms, and their varying inter-relationships, responsible for acute and late normal tissue radiation damage are considered and shown not to relate solely to the time factor. Reports from the literature are used to illustrate these points.

The relative biological effectiveness of fast neutrons (42MeVd leads to Be) for early and late normal tissue injury in the pig.

Early and late radiation damage has been investigated in a number of normal tissues in the pig after irradiation with single doses of neutrons produced by 42MeV deuterons on beryllium. The results have been compared with data obtained after irradiation with single doses of 250kV X rays. In the skin a low RBE value of approximately 1.2 was obtained for the early (3-9 week) epithelial reaction. For the subsequent dermal vascular response, higher RBE values in the range of 1.35-1.6 were obtained: the RBE decreasing with an increase in the neutron dose. For late skin damage, assessed by the relative reduction in the linear dimensions of an irradiated field, a RBE value of approximately 1.5 was obtained. In the kidney the RBE value, for a neutron dose level (550 cGy) at which renal function was just preserved, was 2.0. A lower value of 1.7 was found for doses resulting in a loss of renal function. The results of 133Xenon clearance studies showed two waves of impaired ventilation function in the irradiated lung. In the acute reaction (3-9 months), at a dose level consistent with just preserving normal ventilation function, the RBE value was less than 1.2. For late lung damage (15-24 months) the RBE value was higher, 1.4. For the rectum, methods are presently only available for assessing acute damage. A RBE of 2.0 was found for neutron doses in the range 350-575 cGy. The RBE values for early endpoints in the skin, lung and gut of the pig are comparable with those published previously for other species, including man. The values for late effects in pig skin and lung were higher than for early damage in those tissues.

Seventh interim progress report of the british institute of radiology fractionation study of 3F/week versus 5F/week in radiotherapy of the laryngo-pharynx.

A fresh analysis of the data entered into the multicentre BIR fractionation trial of 3F/week versus 5F/week in radiotherapy of the laryngopharynx has been undertaken. Completed records of the 732 patients initially entered into the trial have now risen from 687 at the last report to 706. The data have been analysed in a manner similar to that adopted previously so as to measure the effects of the two regimes on both tumour and normal tissues, and some additional analyses have now also been made. There have been some modifications in the results in the various sub-groups which may be due to an inadequate number of patients having been followed up for long enough at the time of the previous analyses. More data for late radiation damage to normal tissues and new radiobiological findings have suggested possible explanations for the differences which have emerged between the two groups. The apparent differences between the sub-groups containing patients with highly localized tumours, which were reported in our previous report, are now less marked and not statistically significant.

Granulocyte chalone assayed in vivo in the mouse.

An in vivo system has been developed for estimating the inhibitory activities of granulocyte chalone which overcomes the objection to the use of mixed proliferating target cells. It depends on the identification of labelled mature granulocytes in the peripheral blood of mice that received a radioactive precursor of DNA synthesis, with and without granulocyte extracts, several days previously. Two extracts of bovine granulocytes were tested. The first demonstrated that maximum inhibition was achived when it was given 2 h before the isotope, suggesting that its activity was short lived. It also failed to depress the labelling index of peripheral lymphocytes, thereby demonstrating tissue specificity. The second was used to show that the dose-response relationship was exponential.

Late radiation damage to pig skin.

The severity of skin contraction in a previously delimited treatment field has been used as a measure of late radiation damage to pig skin. Total treatment doses were given as 6, 14, and 30 fractions over 39 days or as 6 fractions over 18 days. Iso-effect curves for severe linear field contraction showed that no simple mathematical formula could be used to calculate safe "tolerance" doses when fractionation regimes were modified. The results do indicate that for a given level of acute damage, late damage was increased by changing from 5 to 2 fractions per week. These findings are similar to those obtained from surveys in man.

Hyperbaric oxygen and radiotherapy: a Medical Research Council trial in carcinoma of the bladder.

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.

Hyperbaric oxygen and radiotherapy: a Medical Research Council trial in carcinoma of the cervix.

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.

Sixth interim progress report of the British Institute of Radiology fractionation study of 3F/week versus 5F/week in radiotherapy of the laryngo-pharynx.

The results are reported of the multicentre BIR fractionation trial of 3F/week versus 5F/week in radiotherapy of the laryngo-pharynx. 687 patient records have been analysed with respect to survival rates, recurrence-free rates and laryngectomy-free rates. For the group as a whole these analyses show no difference between the two fractionation regimes. Analysis of the sub-group which had early disease confined to the vocal cords does, however, show a better recurrence-free and laryngectomy-free rate for those patients treated with 5F/week, though the survival rate for the two groups remains similar. Acute and late normal tissue reactions are reported for up to six years after treatment. It appears that treatment with 3F/week can be given safely to patients with advanced disease. The differences between the two treatment groups who had early disease of the vocal cords are discussed, but until more data become available in the future the problems raised cannot be resolved.