Acta Oncologica

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The 1991 Elis Berven Lecture: Radiotherapy in the Nineties: Increase in cure, decrease in morbidity Stanley Dische To cite this article: Stanley Dische (1992) The 1991 Elis Berven Lecture: Radiotherapy in the Nineties: Increase in cure, decrease in morbidity, Acta Oncologica, 31:5, 501-511, DOI: 10.3109/02841869209088298 To link to this article: https://doi.org/10.3109/02841869209088298

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A C T A O N C O L O G I C A Vol. 31 No. 5

1992

THE 1991 ELIS BERVEN LECTURE

RADIOTHERAPY IN THE NINETIES Increase in cure, decrease in morbidity STANLEYDISCHE

Advance in radiotherapy can be achieved by obtaining a greater tumour control and by reducing the morbidity of treatment, both early and late. The factors influencing both means of benefiting the cancer patient are considered.

Reading of Elis Berven I do think he would have approved the title of this lecture for, undoubtedly, when he led the Radiumhemmet between 1923 and 1950 these were his objectives. All cancer treatment is designed, firstly, to cure the patient but, secondly, to do so with the minimum of stress and morbidity. Restoration of appearance and function to normality must be goals of equal importance in the eradication of tumour in cancer management. We live in a society where quality standards are continually being raised. The public expects to be cured of their cancers and restored to normality. Although our patients may remain grateful. they are certainly more critical, more concerned with possible side-effects and less ready to accept morbidity as a price to pay for the cure of their cancer. Important in recent years has been the recognition that considerable late radiation change can develop after many standard treatments, and can be more marked than originally recognised. Although a risk of up to even 5% of serious late morbidity may be justified when radiotherapy is used for treatment of an advanced tumour in the head and neck region, where there is no alternative approach to cure. such an incidence is totally unacceptable where radiotherapy is used as an adjunct to surgery, as in the

Presented as Bristol-Myers' 'Elis Berven Lecture' at the Annual General Meeting of the Swedish Society of Medicine, November 27, 1991, Stockholm, Sweden. From The Marie Curie Research Wing for Oncology, Mount Vernon Centre for Cancer Treatment, Mount Vernon Hospital, Northwood, Middlesex HA6 2RN, UK. Correspondence to: Professor Stanley Dische, address as above.

management of early breast cancer where thc risks should be barely measurable. We can make advanccs in our field equally by reducing the risks of morbidity as by increasing cure. We know particularly with the contributions of Ingela Turesson et al. ( I ) how radiation changes, once they appear in the first few years after treatment, will progress (1). Recent studies here in Stockholm have suggested that there may be some disturbance of well-being in the early years after radiotherapy but, of course, there are multiple factors operating in such cases and we must be careful to keep all in perspective (2). We can see the challenge in Fig. 1 which shows a patient with a rapidly progressing squamous cell cancer of the alveolar buccal sulcus. The alternatives of management are surgery and radiotherapy with, or without, the addition of cytotoxic chemotherapy. If we are to employ radiotherapy there are many vital structures to be of concern: the skin, mucosa, lower jaw and salivary glands among them. Acute reactions may be troublesome, but with most standard regimens of radiotherapy they settle and it is the late changes which are really dose-limiting. Although we have well-recognised criteria for tumour control, those for measuring and recording morbidity have not reached a consensus and there is a very wide variation in the way late radiation effects are reported. The Radiation Therapy Oncology Group/European Organisation for the Research and Treatment of Cancer system has been available for more than 20 years, but it is still only used by a minority of radiation therapists reporting late effects. It is a valuable system but suffers, like the 50 1

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Fig. 1. A lady of 62 years presented with a rapidly growing carcinoma in the alveolar buccal sulcus (a). When first seen the tumour was already bulging and infiltrating the tissues of the overlying skin (b). During a period of 17 days. while we investigated and planned our management. the tumour obviously grew, extending over the alveolus and into the epidermis (c).

TNM system, from being made up of a complexity of different features. Grading is determined from a mixture of symptoms, signs, the use of medicines and radiographic appearances. Surely in this computer age, where data can be itemised and readily recorded, each of these features should be separately measured and recorded. Although there are more individual observations to make, it is a simpler and more precise process. Later the data can be analysed and the best combination of these individual items extracted and used for comparison of effects. We proposed such a system and a number of meetings of a small International Working Party, initiated by the Medical Research Council, has moved the project along but progress has been slow (3). Every sciencific activity is furthered when we have precise and agreed measurement and this is one of pressing importance. How can we, looking towards the turn of the century, minimize this late change? (Table I). Advances in radiobiological science, in particular the contributions of many prominent in the field, including Eddie Barendsen (4) and Jack Fowler, (5) led to the wide adoption of the linear quadratic equation as the best method of prediction of the relationship between radiation dose and effect. We have

the a component where there is a linear relationship and the /I where it is quadratic. Whereas in tumours and early-responding tissues the a component appears to dominate, in late-responding tissues there is a large /I element, therefore, the giving of radiation in many small doses should spare late damage and, or course, conversely, largedose fractions should be associated with a greater risk of injury. Total dose dominates tumour control, but in normal tissues the total dose and the individual fraction size are both important (Fig. 2) (6).

Table 1 Possibilities of limitation of lute rudiution injury

I. 2. 3. 4. 5. 6.

I. 8. 9. 10.

Carefully devise overall plan of management and case selection for radiotherapy Balance the magnitude of benefit against the risk of injury Determine tumour spread and limit volume for treatment Radiotherapy should be planned in fine detail Maintain a high quality of delivery Determine individual radiosensitivity Moderate acute morbidity Employ a small radiation dose per fraction Use a shrinking field technique Attempt to possibly moderate late injury

RADIOTHERAPY IN THE NINETIES

Hyper-

1'6

$

H

g

1

.8 .6

I

1

3

4

Dose per fiaalw @y) Fig. 2. A diagram based upon work by Withers el al. (6). and

modified by the author and Dr. M. Joiner. illustrates the importance of the .//I ratio in determining the effect of changing the dose per fraction. Efects are normalised at a 2 Gy dose fraction. The shaded areas represent reasonable ranges for many late responding tissues (.//I 1-4 Gy) and acutely responding tissues (ct//I 8 - 1 5 Gy). Varying the dose per fraction causes very little alteration of effect in tumour. but a great deal in the late effects in normal tissues. Lowering the fraction size below 2 Gy should lead to a very considerable sparing of late changes in normal tissues while maintaining tumour control.

In clinical practice can the linear quadratic equation be supported by clinical experience? We now have a number of clinical studies, including randomised trials where smalldose fractions have been employed, and it is indeed clear that much higher total doses can be achieved by giving small individual doses. It was of course in an early trial here in Sweden reported by Edsmyr and his colleagues ( 7 ) that it was shown that a higher total dose could be achieved in bladder cancer with comparable late morbidity by hyperfractionation and. further, such an increase in dose did give increased long-term tumour control and survival. There are now three studies in head and neck cancer where the giving of small dose fractions of around 1.1 Gy has enabled the total dose to be increased by 10 Gy or IS'% (8-10) and in two of these this appears associated with an increase in tumour control (8, 9). On the other hand we have seen the harmful effects of large-dose fractions, particularly in the central nervous system; clinical observations in Norway. as well as at Mount Vernon. have confirmed a high incidence of radiation myelitis with high dose per fraction and it has also been observed in other tissues ( 1 I. 12). Some, however, have performed clinical studies and have reported that, provided a dose reduction is made, similar tumour control can be achieved without apparently increasing morbidity. Henk & James ( 13) and Weissberg et al. (14), found that large doses per fraction were successful in achieving all that multiple small doses could achieve. while the incidence of morbidity was similar. When we look at these studies in the light of modern knowledge of tumour cell kinetics there is the complicating factor that

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acceleration of treatment was achieved in both these studies. We can postulate, therefore, that the acceleration of treatment. with the consequential reduction of time for repopulation, largely balanced the reduced cell-kill resulting from a reduction in the total dose necessary to keep the risk of morbidity at the same level as with conventional therapy. The British Institute of Radiology Trials Group performed two studies which included in all 1 345 patients and concluded that the modification of radiotherapy, tirstly. by using a smaller number of fractions and, secondly. by treating over a short duration can be equally successful as more demanding schedules with many individual treatments and greater overall time (15, 16). These early studies did employ features of design which can be questioned. Each centre was allowed to choose its own dose level and total dose reduction when moving from 5 to 3 fractions, and so the British Institute of Radiology Trials are really collections of small individual trials; such studies lead to great variance and poor sensitivity and might best be analysed using a n overview technique. Even then there is evidence in the British Institute of Radiology Trials which is compatible uith our current concepts of fractionation. For example. in the multivariate analysis of the data in the trial of 5 versus 3 fractions a wcck. tumour control atid the need for laryngcctomy is better in the 5-fraction group with relative risks bcing 1.14 (confidence limits 0.92- I .43) and 1.21 (0.88- I .67) (Table 2 ) . Such margins, if they were statistically significant, would certainly persuade the clinician and the patient towards multiple fractions. We can also gain further evidence by careful study of the structural changes and of altered function in our patients (treated with different fractionation regimens). The parotid is important to the flow of saliva in the mouth and, in turn, the integrity of the teeth and preservation of swallowing Function. We have investigated the relationship between fractionation and the function of the parotid, a year or more after treatment, in patients where one parotid was fully irradiated within the target volume, but where the other was spared (17). The salivary flow was stimulated by lemon juice placed upon the tongue and the secretions from each individual parotid measured over a period of 710 min. There was a wide normal variation in the stimulated flow rate from one patient to another, but in any one there were closely similar flows from both glands and so in patients treated unilaterally the untreated side could act as a control. Twelve patients received radiotherapy in conventional 2 Gy fractions to doses of approximately 66 G y and the mean flow was reduced to only 20% of that of the untreated glands. The 8 patients given a similar dose increment to 4 0 G y in the management of lymphomas showed only a modest reduction to 63% A group of 6 patients treated with continuous. hyperfractionated, accelerated radiotherapy ( C H A R T ) where 1.5 Gy fractions

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Table 2 The relative risk ratios with 95% confidence intervals are shown for the two British Institute of Radiology (BIR) trials. There are some margins which, if statistically significant, would have clinical importance and influence management towards 5 fractions and larger treatment periods. The structure of the trial led to a large variance

BIR trials-Multivariate

analyses

~~

Local tumour free

Survival Risk of laryngectomy

Trial 1

Trial 2

3 or 5 f/week Relative risk 3 v 5

4 weeks or > 4 weeks Relative risk short v long

1.14 (0.92-1.43) 1.05 (0.87- .27) 1.21 (0.88- .67)

1.10 (0.84-1.44)

were used to a total dose of 54 Gy showed a mean flow of 57%, inseparable from the conventionally treated low-dose group. This, therefore, gives us good evidence that small fraction size is indeed sparing of late change in the parotid gland. Observation of postradiation change using the system in which items are individually recorded has also shown a trend towards reduced late change in patients treated with CHART; though in this comparison much more advanced disease was treated by CHART; some of the changes were possibly related simply to those which follow regression of a large tumour mass ( 18). We can conclude that the bulk of evidence from the clinic, therefore, is in favour of the view that the linear quadratic equation is reliable when used to forecast the incidence in late damage and that the use of small doses per fraction spares late radiation damage. Animal models are important to advancing knowledge in radiobiology, but it is in the human that we finally need to advance our knowledge so that we can safely apply it to benefit our patients. We feel that the parotid work has shown the direction to pursue and have recently developed plans to observe, in a similar way, the skin. Jim Morris from Vancouver, working in our Research Wing, has developed a system for counting the number of sweat glands before and after radiotherapy (19). This technique employs a latex impression of the skin surface after stimulating the sweat glands by iontophoresis of pilocarpine. It appears that we have a dose-response relationship and, most importantly, can detect a significant reduction in the number of sweat glands in skin which has received radiation doses as low as 30 Gy in 2 Gy fractions and where the appearance is entirely normal by naked eye examination. Using this and other tests for sweat gland function it should be possible to make a comparison of different dose fractionation regimens and obtain hard data concerning late changes in skin in the animal most relevant to clinical practice-man. The modification of acute radiation reactions, particularly in the mucous membranes, is now an area of active research. Maciejewski et al. (20) have shown that stimula-

1.23 (0.96-1.59) 1.01 (0.70-1.45)

tion with 2% silver nitrate solution prior to therapy can moderate the reaction subsequently seen with external beam therapy. From New Zealand has come a report that steroid mouthwashes can prevent radiation reactions appearing in the mucosa during conventional radiotherapy (21). We have found the latter technique to show some promise in our patients receiving accelerated radiotherapy and an investigation is proceeding. The use of surface-acting radioprotectors such as WR 2721 is another possibility. The moderation of acute reaction in mucosa by surfaceacting effects presents an important area for improvement in clinical radiotherapy. In conventional radiotherapy the 24-h interval appears to give time for all repairable damage to be complete, but when we move to more than one treatment in a day we must leave adequate time for repair to occur. Practical considerations suggest as short a time as possible, but the shortest interval-2 h-was used by NGuyen et al. (22) in head and neck tumours with disastrous results; they also gave up to eight treatments a day and so there was probably an increasing accumulation of unrepaired damage through the day. Other workers have employed intervals of 3, 4, 6 and 8 h. The work of Cox et al. (10) has clearly suggested than an interval greater than 4.5 h in head and neck tumours gives rise to less late damage than shorter intervals. We can conclude that 6 h would seem desirable and 8 h might be better if it can be achieved; however, the further advantage is probably small. There is, however, one tissue which shows an exceptional pattern of late effects when multiple treatments are given in one day, that is the central nervous system and, in particular, the spinal cord. We have encountered four cases of radiation myelitis when using the CHART regimen in which three treatments are given at 6 hourly intervals each day for 12 consecutive days, with doses at the spinal cord calculated to range from 45 Gy to 48 Gy (23). This incidence is in direct contrast to the original prediction that the risk of central nervous system injury would be reduced since 1.5 Gy doses were employed. New biological experiments, stimulated by clinical experience, have suggested

RADIOTHERAPY IN THE NINETIES

that there is a component of repair of injury in this tissue which is considerably longer than in others and its halftime may exceed 4 h. If, therefore, a period of less than 24 h is employed total doses to the spinal cord must be reduced (Chassagne, personal communication, 1991). In clinical practice one encounters patients who show treatment reactions unusually early, or of unusual severity. We do know that there are certain patients with rare hereditary conditions, such as xeroderma pigmentosa or with collagen vascular diseases who have a reduced capacity to repair radiation injury. There are systems for determination of inherent radiosensitivity using fibroblasts in culture. A larger proportion of patients may have a more modest but, nevertheless, clincally relevant, increased sensitivity. A new technique gives promise of a quicker and easier way of determining the radiosensitivity of normal tissues. (Hodgkiss & Joiner, personal communication 1991). In addition to the moderation of acute radiation responses we must consider the moderation of late responses. We have noted, over a long period of years, a few patients who have shown unusually marked postradiation change associated with hypothyroidism. The administration of thyroid hormone has led to a marked resolution of these changes. Joiner et al. (24) working in the Gray Laboratory have explored pentoxifylline as a possible moderator of late injury. We must not be content to watch severe late changes develop in patients without exploring the possibilities of their amelioration. Turning to the response of tumour (Table 3), it is sometimes suggested that all our efforts to improve primary tumour control, particularly in advanced disease, will be of little avail as the appearance of distant metastases will abbreviate the duration of any benefit thus achieved. My colleague, Michele Saunders, has analysed our series of patients treated with CHART in head and neck and lung cancer looking to the importance of local tumour control (25, 26). In a pilot group of 98 patients with relatively advanced squamous cell cancer of the head and neck it was noted that all who responded to the primary course of treatment, and stayed locally free of tumour, did

Table 3 To improve cure by radiotherapy

I . Improve primary control so reducing metastasis 2. Determine tumour spread so as to include in volume for treatment 3. Radiotherapy should be planned in final detail 4. Maintain a high quality of delivery 5. Measure inherent radiosensitivity 6 . Exploit tumour hypoxia 7. Add cytotoxic agents 8. Accelerate treatment-tumour cell kinetics 9. Integrate methods to improve radiotherapy 10. Improve the clinical trial of new approaches

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well in the long term and none showed evidence of metastasis. The highest incidence of metastases was seen in the patients where the primary tumour failed to resolve, while those where the tumour resolved, only to recur at a later date, proved an intermediate group (25). With lung cancer the irrelevance of primary tumour control to survival is often stressed yet, even here, treating a group of 70 patients with locally advanced carcinoma of the bronchus, 14 of the 28 who achieved and maintained local tumour control, remained long term free of metastatic disease (26, 27). Primary tumour control is important to prevent distressing death due to uncontrolled local disease, or the need for very wide, disfiguring and disabling surgery, but it also may reduce the incidence of distant metastases and so increase survival (26, 28). Some of the important ways to compare local tumour control, including determination of tumour spread and the planning and quality of radiotherapy, have been considered under the limitations of late-radiation injury, but they are of equal importance here. Again, one must plan the overall management and coordinate the contribution of surgery and cytotoxic chemotherapy as well as of radiotherapy in order to gain the greatest chance of cure. One must recognise that the larger the bulk of tumour the greater difficulty we will have in eliminating all neoplasm and surgery is an extraordinarily good debulker or tumour shrinker. Where clinical experience indicates a low probability of tumour control by radiotherapy there is a greater indication for surgical debulking whenever possible. In the last few years we have seen a number of interesting attempts to determine the radiosensitivity of human tumours in vitro and to compare such measurements with the response observed clinically. The use of the Cam assay has excited great interest due to the high success rate of the culture system and of the relative speed with which the result may be produced. The main group of patients studied at Houston were given radiotherapy after surgery for advanced head and neck tumours (29). So far the correlation with clinical outcome has just hovered at the edge of statistical significance and we must wait a greater experience. In Manchester, using a more conventional approach to cell culture in carcinoma of cervix, there appears early in the study to be a fairly good correlation between inherent sensitivity and the result observed (30). The field remains an experimental one and we await the development of further advances in technique and the definitive results of present studies. The radioresistant hypoxic tumour cell has been the target of much laboratory and clinical research. A large clinical effort was expended in the clinical trials of hyperbaric oxygen, metronidazole and misonidazole (31). Attention has now been focussed on a second generation of trials of the chemical sensitizers-nimorazole, etanidazole and pimonidazole-the results of which are now becoming available. The more potent sensitizers have so far been

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disappointing, for pimonidazole failed to give benefit in carcinoma of cervix (32) and a European study with etanidazole in head and neck cancer has so far shown only a small margin of improvement which is far from significant (Chassagne, personal communication, 1991). Results of a similar American study are not yet available. On the other hand, nimorazole, a low toxicity drug has shown, in a particularly well-planned and constructed randomised trial performed in Denmark, a margin of benefit at least as great as that previously achieved with misonidazole in the same group of patients-the supraglottic and pharyngeal carcinomas (Overgaard, personal communication 1991). Jens Overgaard has recently presented the results of an overview of all the trials of methods to achieve hypoxic cell radiosensitization, which includes just under 10 000 patients. A clear advantage in local tumour control and even in survival has been demonstrated (Overgaard, personal communication 1991). This benefit seems to extend through all the main methods employed- hyperbaric oxygen, chemical sensitizers and all the main sites under study, although only at a significant level in the head and neck. This does certainly encourage the view that hypoxic cells do really matter in clinical radiotherapy and that sensitization can be achieved. The margins so far, compared with toxicity, have never been sufficient so as to justify their incorporation in routine clinical management but nimorazole may, in the the management of supra-glottic and pharyngeal carcinomas, be the first exception. During the long period of our endeavour with hypoxic cell radiosensitization there has been a great deal of development in radiobiology which is important to hypoxia. The tumour which is hypoxic may be one with a capacity to rapidly proliferate and so outstrip its blood supply and lead to tumour hypoxia. In the pimonidazole trial in carcinoma of the cervix (32), patients were treated conventionally over 5 weeks with 2 Gy fractions daily and we can readily imagine that the extra cell kill, achieved each day by adding a sensitizer, was negated over the weekends by the cellular proliferation of the surviving tumour cells. To exploit hypoxic cell sensitizers, therefore, we probably need to combine with accelerated treatment. Early in the history of hypoxic cell radiosensitization there were attempts to use carbogen under atmospheric pressure but no significant benefit was achieved (33). There is now evidence from experiments performed by Anamaria Rojas (34) that carbogen is a very effective way of hypoxic cell radiosensitization, giving margins of benefit in all fractionation schedules beyond a single treatment, superior to those achieved previously by hyperbaric oxygen and chemical agents. In the early trials carbogen breathing was commenced 90- 120 min prior to radiotherapy, but the evidence now suggests that the optimum time for carbogen breathing prior to radiotherapy is between 5- 15 min and that after that period of time the benefit is lost. Recently it has been shown that the addition of nicotinamide gives

further benefit, probably by preventing the transient hypoxia which, unlike chronic hypoxia, will not be benefited by means of hypoxic cell radiosensitization with chemical sensitizers and carbogen (35). A workshop was held in 1991 at the Gray Laboratory to discuss a new approach in which nicotinamide and carbogen are given combined with accelerated radiotherapy. This workshop has stimulated a number of phase I and phase I1 clinical trials. There is, in addition, a group of bioreductive agents which are powerful hypoxic cell cytotoxins, some of which have a double effect since they appear to induce severe hypoxia, so increasing their cytotoxic action (36). Such drugs need to be combined with radiation for the oxic cells are not affected, but this combination is different from the hypoxic cell radiosensitization which has been discussed. Phase I trials of the first drug, a Stanford compound, have now just commenced. When there is occasion to watch the growth of an untreated human tumour, volume increase is relatively slow and volume doubling times usually range from 25100 days. This relatively slow progression has led clinicians to the view that cell proliferation during a conventional 40-50 day course of radiotherapy is not of great importance in determining the outcome. Now knowledge of the cell kinetics of human tumours and analyses of clinical material has suggested that there may be a wide discrepancy in events at the cellular level with those which are observed clinically. In the past, it has only been possible to study human tumour cell kinetics in a small number of patients with advanced disease. The use of tritiated thymidine was required with the taking of multiple samples of tumour and the whole process of autoradiography made the procedure a complex one requiring a number of weeks to complete and needing a considerable laboratory effort. In 1985, however, Begg et al. (37), working at the Gray Laboratory, described a technique in which, after a single injection of a small dose of bromodeoxyuridine (BUdR), a biopsy was performed 4-6 h later and then with the use of a flow cytometer the cell kinetics of a tumour were determined within 24 h. With this approach not only can the number of cells actively involved in DNA synthesis, the labelling index (LI), be measured but also the duration of the DNA synthetic period (Ts) can be calculated from the redistribution of the BUdR-labelled cells round the cell cycle in the time between injection and biopsy. From the LI and Ts we can determine the potential doubling time (Tpot) which is a measure of the proliferating activity of the turnour cells, taking into account the presence of dividing and non-dividing cells, but assuming the absence of cell loss. At Mount Vernon, in studies performed in over 500 human tumours we have shown that the Tpot ranges widely from 2-12 days but in some sites, in particular the squamous cell carcinomas in the uterine cervix and in the

RADIOTHERAPY IN THE NINETIES

head and neck region, the majority of tumours can potentially double their cell number in five or fewer days. Spontaneous cell loss, mainly due to differentiation and degeneration, is particularly high in these tumours thus accounting for the 10- to 20-fold difference between the cellular doubling times and the volume doubling times observed clinically (38). When tumour cells are destroyed by radiotherapy or cytotoxic chemotherapy this situation is likely to be greatly altered. When a squamous cell carcinoma is irradiated a 2 Gy dose may destroy half the tumour cells and so at the end of the first week of daily treatment the number of surviving tumour cells may be less than 5% of those existing at the beginning. With cell destruction occurring at such a rate it seems probable that the high spontaneous cell loss occurring in the unperturbed tumour will be greatly reduced and that the tumour cells may realise their full reproductive potential. Furthermore, the cellular population may be accelerated with an increased growth fraction of the surviving tumour cells and possibly a reduction in cycle time so that the repopulation may occur at a faster rate than that suggested by cell kinetics performed prior to treatment. Further evidence to support the view that cellular repopulation may occur at a very rapid rate has been obtained from our studies using an immunohistological technique in which the cells which have taken up BUdR can clearly be seen (39). Considerable variation in labelling can be observed and at the growing edge of squamous cell carcinomas commonly 50-60% appear to contain BUdR and, therefore, would appear to be synthesizing DNA. The advantage of this technique over flow cytometry is that the tumour cells can be readily differentiated from normal cells; this is particularly important in diploid tumours where the flow cytometer cannot differentiate between normal and tumour cells. In squamous cell carcinomas of the head and neck region, the Tpot was calculated using the labelling index determined by immunohistochemistry combined with the duration of S-phase determined by the flow cytometer. Although 46 of the tumours showed a Tpot of less than five days using data entirely derived from the flow cytometer, when the maximum labelling index determined histochemically was used, combined with Ts measured by flow cytometer, in 99% of the tumours Tpots were less than five days and in 89% less than three days (39), so suggesting a very great capacity for cellular repopulation. Analyses of the results of clinical studies also give support to the view that repopulation during prolonged courses of radiotherapy is a cause of failure. In the management of tumours at a specific site, using a standard daily dose in a number of fractions, some variations do occur in the overall duration of treatment. There may be differences in attitude among individual oncologists as to the need for persistence of treatment through reactions and

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some may allow more pauses than others. Further, patients do not always attend regularly for treatment, particularly when reactions develop and then we have, of course, public holidays and machine breakdowns, which may lead to an unplanned prolongation of overall treatment times. Maciejewski and his colleagues were the first to take advantage of such data and they showed in an analysis of patients with head and neck tumours that there was a highly significant inverse relationship between the duration of treatment and the probability of local tumour control (40). In an analysis of 310 patients with T3-T4 squamous cell cancer of the larynx, they found that with patients given comparable doses, as calculated by the NSD equation, local control rates decreased from about 80% when overall treatment times were of the order of 32-35 days to only 16% at 56-63 days. Similar findings have been reported in head and neck tumours (41) skin tumours (42), bladder tumours (43) and recently in carcinoma of the cervix. We must, of course, express some reservation concerning the analysis of data gathered retrospectively, since prolongation of the duration of treatment is not necessarily a random process. Patients with more aggressive and more advanced disease may be more distressed by reactions, and treatment may be more protracted in these cases. However, the size of the effect and the consistency with which it has been demonstrated is impressive. A frequently used technique to facilitate recovery from early reactions has been the split-course-the deliberate introduction of a rest period of one or more weeks during the course of treatment. It has, however, been shown that this prolongation of overall time leads to impaired tumour control, suggesting that repopulation has occurred during the rest period (44).All these analyses give strong evidence that overall time is important to radiation response and, therefore, to the view that cellular repopulation is a major problem in tumour control. In order to accelerate the treatment, that is to reduce the overall duration so as to limit the opportunity for cellular repopulation but also to retain multiple fractions in order to lower the incidence of late radiation change, more than one treatment must be given each day. Early attempts to give 2 Gy fractions three times a day and complete all the treatments in two working weeks yielded a high, and unacceptable, level of acute and late radiation injury, without giving any promise of improved tumour control (45, 46). Some workers have attempted to use a 1.8 Gy dose and some promising results have been reported from New Zealand by Lamb et al. (47). Most workers have felt that the seventy of acute reactions is unacceptable when accelerated courses of treatment are given, without interruption, using conventional doses of 1.8-2 Gy. The difficulties in obtaining a satisfactory total dose when using normal dose increments have led to the use of smaller doses combined with a rest period during treat-

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ment. This was piloted by Van der Schueren and his group (48) and led to a randomised controlled trial under the auspices of the European Organisation for the Research and Treatment of Cancer when over 500 cases were included (49). No benefit in tumour control was achieved and this may be due to the fact that the overall treatment time was as long as that of the control group because the rest period extended to four weeks. In the latest study the rest period has been introduced rather earlier and the treatment restarted in 10 days with the whole course complete within a period of five weeks. This randomised, controlled trial is currently proceeding and includes over 300 patients. We look forward to learning of the results. Other workers have used regimens incorporating a rest period. Wang et al. (50, 51) gave twice daily an individual dose increment of 1.6 Gy and included a rest period beginning in the middle of the third week, but the final boost was completed by the end of six weeks. They, in a retrospective comparison, have shown a significant improvement in the results of treatment at a number of head and neck sites. This regimen is now to be part of the large four-arm study which is to be performed by the Radiation Therapy Oncology Group. In Houston the approach has been to give the boost dose as a second treatment while the main course is being continued (52). The result has been a reduction in the overall duration of treatment from 7.5 to 6 weeks. Following pilot studies, when the boost was given during various phases of the main treatment, it was found that the best results were achieved by giving it during the last two weeks. The results of a pilot study in oropharyngeal cancer are yielding promising results and this technique is now to be incorporated in the Radiation Therapy Oncology Group trial. The hyperfractionated regimen developed by the Radiation Therapy Oncology Group and, most recently, reported by Cox et al. (10) is to be the third experimental arm with conventional radiotherapy as the fourth. At the Mount Vernon Centre for Cancer Treatment, in collaboration with Jack Fowler and Juliana Denekamp at the Gray Laboratory, Michele Saunders and I devised a novel scheme of continuous, hyperfractionated, accelerated radiotherapy (CHART) with the objective of combining the greatest chance of eradicating all tumours with the minimum of late effects in normal tissues (53). It was considered that there should be no interruption to permit repopulation and, once commenced, treatment should be continued every day to its conclusion. In the head and neck region all regimens of accelerated radiotherapy result in the appearance of marked mucosal reactions on the 13th or 14th day and, therefore, it seemed best to complete treatment before that time; in this way there would be no problem of attempting to continue through reactions and they would be allowed to heal without the inhibition of further irradiation. During such a short overall period of treatment little, if any, repopulation of tumour cells would

be permitted to occur. Radiotherapy was given three times each day, with 6 h between fractions, on 12 consecutive days including one weekend. A pilot study was commenced in January 1985 giving each of the first 38 patients a dose of 1.4 Gy on 36 occasions so as to achieve a total minimum tumour dose of 50.4 Gy. As tolerance appeared good, the individual dose was increased to 1.5 Gy and a total dose of 54Gy was then achieved. A total of 263 patients were entered into the pilot study which was concluded in March 1990 when randomised trials were commenced (25). The radiation reactions which appeared soon after treatment were marked but, on the whole, well tolerated. In some cases final healing of small areas of mucosa was delayed for several months, but all finally resolved. Apart from the four cases of radiation myelitis already discussed, other normal tissues showed the anticipated sparing of late change. The reduction of dryness of mouth observed clinically was confirmed by the investigation of parotid function already described (17). In the pilot study 92 patients with squamous cell cancer at one of the major sites in the head and neck region were included (25). For these patients a comparison of results has been made by matching with those previously treated by conventional radiotherapy by site and T and N stage. A lifetable analysis has shown that primary tumour control was 67% at two years compared with 44% in the conventionally treated group (p = 0.OOOl). Considering the 71 patients with T3 and T4 tumours, control in the primary site and lymphatic drainage was 54% with CHART compared with 31% for conventional radiotherapy; the 2-year survival was 56% after CHART compared with 44% after conventional radiotherapy. The results observed in 76 patients with primary bronchial non-small cell carcinoma have been compared with a previously treated group of 62 patients with similar tumours. There was clearance in 40% of CHART patients compared with 16% in the previous group. A 2-year survival of 32% with CHART can be compared with 12% of the previous patients (25). After considering these findings a joint Medical Research Council, Cancer Research Campaign and Department of Health initiative established multicentre trials in bronchial and in head and neck tumours to compare CHART with conventional radiotherapy. The trials were fully opened in April 1990 and by the 31st December 1991, 625 patients were included in 12 co-operating centres, including one here in Sweden with another shortly to join us. The trial is planned to include a total of 1350 patients by the end of 1993. There has, in the past, been a tendency to concentrate upon a single factor affecting the response to radiotherapy, anticipating that a major advance will occur just by a single manipulation. The story of hypoxia and the means to sensitize resistant hypoxic cells is one example. In these trials there was even a tendency to alter other factors for the convenience of the technique as, for example, with

RADIOTHERAPY IN THE NINETIES

Fig. 3. The patient described in Fig. I was treated by CHART and there was complete regression and a good functional and cosmetic result is apparent

hyperbaric oxygen. where a limited number of fractions were used because of the complexities of the technique. We now realise that we cannot look at any one determinant of radiation response in isolation and that all the factors which may influence radiosensitization must be recognized. Hypoxia, rcpopulation and inherent radiosensitivity are recognised as important in determining the response of tumour to radiotherapy. We must develop methods to predict the importance of all these factors in any one case and then devise the optimum schedules of treatment. The knowledge of tumour cell kinetics derived from radiobiological studies has importance to the whole of oncology and to the combination of modalities. The majority of attempts to improve the results of radiotherapy by combination with cytotoxic chemotherapy have featured a gap of three or four weeks between the end of chemotherapy and the beginning of radiotherapy. One must expect that in such a period a rapid repopulation of tumour cells will occur in many sites. It follows that success will only be achieved when chemotherapy and radiotherapy are synchronous or separated by very short intervals. In certain sites the technique of the combination of external beam therapy with brachytherapy is one of the most successfully employed in radiation therapy. Here again gaps may occur between external beam therapy and intracavitary therapy. We may indeed be influenced by the gross shrinking of tumour, and deliberately leave a gap for this to occur. However, while a tumour is visibly shrinking rapid repopulation may be occurring at the cellular level. We have successfully incorporated implantation and intracavitary treatment with CHART by replacing the small volume boost, given on the last 2-3 days. This is all possible because reactions d o not appear until after all the treatment is complete. Our patient with the rapidly progressing carcinoma of the alveolar buccal sulcus was treated by CHART. Tumour regression was achieved and at 2 years a good cosmetic and functional result was apparent (Fig. 3). The only radiation change visible is some telangiectasia and it

is interesting that when observed at 5 years this telangiectasia is, if anything, less evident. Further. the appearance of the skin seems to continue to improve and it is not easy at first sight to see on which side the tumour was placed. She wears her dentures without any difficulty and had to be dissuaded from leaving them in at night. We can, of course, illustrate any point with a single case and one needs the long-term follow-up of a large randomised trial. There is, however. in this case, where the schedule of treatment was based upon radiobiological research, an indication that new schedules of radiotherapy have the potential to improve radiotherapy with better tumour control and lowered morbidity. REFERENCES 1. Turesson I, Thames HD. Repair capacity and kinetics of

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