Europ. J. Cancer Vol. 10, pp. 381-383. Pergamon Press 1972. Printed in Great Britain

Registration of Clinical Data and

Criteria for Selection of Patients for

Fast Neutron Trials

WILLIAM DUNCAN

Department of Radiotherapy, Western General Hospital, Ediburgh EH4 2HU, England

Abs t rac t - -The difficulties of conducting satisfactory clinical trials of fast neutron therapy are outlined. There is a need to establish an organisation for collaborative multi-centre trials to provide evidence of objective evaluation of fast neutron therapy in a reasonable period of time. A minimal list of variates is suggested for record purposes in such collaborative trials. It is also advised that a registry of late radiation morbidity be maintained to ensure early recognition of any associated untoward effects of fast neutron radiation.

IT HAS BEEN shown by the presentations today that fast neutrons may be used in the manage- ment of cancer patients with reasonable safety and produce impressive regression of large tumours [1].

I t yet remains to be seen whether fast neutrons offer any real improvement compared to the use of photons, electrons or protons in cancer therapy. The yardstick is the measure of local control of tumour in the treated area compared with the level of normal tissue reaction produced, particularly late high-dose effects or normal tissue necrosis. Can neutrons increase the therapeutic ratio ?

The difficulties of conducting random clinical trials of fast neutron therapy were well discussed at the first meeting at Rijswijk [2]. The problems fall into four categories; ethical, biological, physical and statistical.

The ethical considerations demand a value judgement to be made of the benefit the patient may obtain from the new radiation compared to a conventional radiotherapy programme. At the present time only patients who have a low probability of cure are con- sidered suitable for such trials of fast neutrons

Accepted 15 March 1974.

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and they are less than ideal clinical material. The biological criteria of importance include an influence that foci of anoxic cells may be present in the tumour and that anoxia may determine a poor response to X-rays. The tumour has to be locally advanced and yet have a low probability of having shed distant metases. A reasonably long expectation of life is required to allow for an adequate period for assessment of radiation effects after treatment.

The physical factors concern both the tumour and the t reatment facility. Firstly the tumour should be accessible to allow its response to be measured. The location of the tumour must be such that adequate depth--dose and dose-rates may be obtained from the neutron facility and an arrangement of t reatment fields possible to provide good distribution of dose around the cancer.

Finally the statistical problem is simply one of obtaining sufficient numbers of patients in such a clinical trial to be able to come to a significant conclusion about the merits of the new treatment in a period of, say, 5-7 years.

These problems are not readily overcome and it would seem that solutions may have to be found in co-operative multi-centre trials. I should say, at once, that where it is possible for

382 William Duncan

a single radiotherapy unit to undertake defini- tive clinical trials independently, then they should be given every encouragement to do so because of the obvious advantage of interval consistency in their management and assess- ment. However this is not possible in the evaluation of three specific areas of the invest- igation into the use of fast neutrons.

Firstly the evaluation of the effects of fast neutrons on uncommon tumours which respond poorly to l ow-LET radiations (Table 1), requires collaborative trials.

Table 1. Evaluation for fast neutron therapy

Ucommon turnouts suitable for co-operative trials

Malignant melanoma Metastatic teratoma testis Osteogenic sarcoma Soft tissue sarcoma Post-cricoid carcinoma Salivary gland carcinoma

Secondly if preliminary clinical investiga- tions show that real improvement is obtained in patients with locally advanced tumours, studies will later have to be made of the effects of fast neutrons compared to X-rays on early cancers which have a high probability of cure by X-rays. I t is obviously important in this situation to have such large numbers of patients that an answer be obtained as soon as possible and this can only be realised by collaborative clinical trials.

As Dr. Catterall has shown [1] to illustrate a significant difference of 15% in local control rate, from 10 to 25%, less than 50 patients are required in the treated and control groups. When we come to put neutron therapy to the test in the management of early cancer of the larynx in which an 80% cure rate is presently expected using X-rays, demonstration of an improvement at this level of only 10% requires over 200 patients in both the experimental and conventionally treated groups.

I have mentioned two reasons for requiring collaborative clinical trials--firstly in order to gain experience in the t reatment of rare t umour s - - and secondly, in order quickly to conduct definitive trials in patients with common tumours which have a high probability of cure.

There is a third and no less important reason for establishing a co-operative organisation; that is to provide a registry of radiation morbidity. This is especially important when

individual centres will have small number of long terms survivors following initial clinical trials. It is only by collecting and collating the data from world-wide experience that one can hope to learn of any important intermediate or late complications.

When I was given this topic, the organisers asked me to consider five topics:

1. Information about patients 21 Information about tumours 3. Details of t reatment schedules 4. Evaluation of tumour effects 5. Measurement of normal tissue responses I feel that the data collected in any initial

co-operative study should be limited and I have prepared what I regard as a minimal list of variates, so that the clerical burden of colla- borators is reduced to the registration of essential data.

First of all there is the basic administrative data of the patient's name, age and sex with a record of the collaborating hospital and radiotherapist. Table 2 lists the information required about the tumour; the site of origin, the histological diagnosis and a record of the international T N M staging. The t reatment state indicates if the tumour is previously untreated, or post-operative, had previous X-ray therapy or perhaps cancer chemothe- rapy. It is important that there be a brief statement of tumour site to be treated, whether it be primary, lymph nodes or other metastatic lesion.

Table 2. Evaluation of fast neutron therapy

Clinical data

Organ/Tissue Histological diagnosis Stage T N M Treatment state Primary } Nodes Site and size Metastases

Table 3 concerns t reatment data required for assessment of results. Details of the site treated, with a note on whether the t reatment includes the pr imary alone, pr imary together with nodes, lymph nodes alone or another metastatic site.

Then is recorded the treatment technique, field sizes used and a calculation of the high dose volume. We also require a record of the t reatment facility and scheme of fractionation stating the number of fractions, the interval of time between fractions and the overall time.

Registration of Clinical Data and Cn'ten'aJ~r Selection o f Patients for Fast Neutron Trials 383

Table 3. Evaluation of fast neutron therapy i i i

Treament data

Site Treatment facility Field size High dose volume Number of fractions Tumour dose Normal tissue dose Critical organ dose

T : T + N : N : M

Technique Date of Ist treatment

Interval Overall time Central Maximum Minimum

Maximum Maximum

The tumour dose is then recorded together with the maximal normal tissue dose and the dose received by a critical organ.

A record of the follow-up data must include the patients survival or date of death and a note of the state of the treated tumour and other related disease. Finally an assessment of radiation morb id i ty - -ear ly and late react ions-- should be recorded.

At the present time most clinical trials record the turnout response in an "all or none" way indicating complete regression or the presence of residual disease. When so many advanced turnouts are being treated in these trials I feel much valuable information may be lost if we continue to record results in this way.

[ think it would be rewarding to devise and use an arbi trary scale to record tumour response. The assessment would not be wholly subjective as accurate measurement of tumour dimensions either directly or radiographically may be possible in most patients.

In certain departments more detailed quanti- tative studies may be made following the example work on the response of lung metastases by treating subcutaneous metastases of bowel and breast cancers.

Finally we have to consider the measurement of normal tissue reactions where it seems perfectly valid to use arbi tratry scales for skin and mucosal reactions, which have already been used in many centres. It cannot be too highly stressed that the detailed assessment of

normal tissue reactions are as important as assessment of tumour response in evaluating a new form of treatment. Normal tissue reactions must be equated in both groups of patients in the trial. Only then can a real improvement in turnout control be established.

Much discussion has centred on the topic of the high RBE values which have been found with low doses of fast neutrons. It is therefore important that the evaluation of fast neutron therapy includes a registry of inter- mediate and late effects (Table 4). This would provide, if all centres using neutrons clinically would co-operate, an early warning system to ensure that any untoward effect may be detected quickly and its relationship to this new form of t reatment either confirmed or refuted. Without such co-operation it will be impossible for individual centres to determine any significant "cause and effect" relationship for a long time indeed.

Table 4. Evaluation o f fast neutron therapy i

Late radiation effects

Skin and soft tissue damage Lens opacification Hypoplastic anaemia Leukaemia Neoplasia Gonadal response

It is still unknown if fast neutrons do increase the therapeutic ratio in the management of cancer and ff this is shown its indications will have to be carefully defined. This is only likely to result if close collaboration develops between centres interested in this experimental work. In addition the careful collection of data will certainly also be rewarding in improving our understanding of the action of X-rays and perhaps also result in their more rational application, as well as being essential for the objective evaluation of fast neutron therapy.

I. M. CATTERALL, The treatment of advanced cancer by fast neutrons from the Medical Research Council's cyclotron at Hammersmith Hospital, London. Europ. J. Cancer 10~ 343. (1974).

2. Proceedings of the 1st Meeting on Fundamental and Practical Aspect of the Application of Fast Neutrons in Clinical Radiotherapy. Europ. J. Cancer 7, 97-267 (1971).