01 introduction

Introduction: the significance of radiobiology for radiotherapy

1.1 THE ROLE OF RADIOTHERAPY IN THE MANAGEMENT OF CANCER

Radiotherapy is one of the two most effective treatments for cancer. Surgery, which of course has the longer history, is in many tumour types the primary form of treatment and it leads to good therapeutic results in a range of early non-metastatic tumours. Radiotherapy has replaced surgery for the long-term control of many tumours of the head and neck cervix, bladder, prostate and skin, in which it often achieves a reasonable probability of tumour control with good cosmetic results. In addition to these examples of the curative role of radiation therapy, many patients gain valuable palliation by radiation. Chemotherapy is the third most important treatment modality at the present time. Following the early use of nitrogen mustard during the 1920s, it has emerged to the point where upwards of 30 drugs are available for the management of cancer, although no more than 10-15 are in common use. Many patients receive chemotherapy at some point in their management and useful symptom relief and disease arrest are often obtained.

The following is a brief outline of the role of radiotherapy in six disease sites:

Bladder the success of surgery or radiotherapy varies widely with stage of the disease; both approaches give 5-year survival rates in excess of 50%.

Breast early breast cancers, not known to have metastasized, are usually treated by surgery and this has a tumour control rate in the region of 50-70%. Radiotherapy given to the chest wall and regional lymph nodes increases control by up to 20%. Hormonal therapy and chemotherapy also have significant impact on patient survival. In patients who have evidence of metastatic spread at the time of diagnosis, the outlook is poor.

Cervix: disease that has developed beyond the in situ stage is often treated by a combination of intracavitary and external-beam radiotherapy. The control rate varies widely with the stage of the disease, from around 70% in stage I to perhaps 7% in stage IV.

Lung: most lung tumours are inoperable and in them the 5-year survival rate for radiotherapy combined with chemotherapy is in the region of 5%.

Lymphoma: in Hodgkin's disease, radiotherapy alone achieves a control rate of around 50% and when combined with chemotherapy this may rise to 80%.

Prostate: where there is evidence of local invasion, surgery and radiotherapy have a similar level of effectiveness, with 10-year control rates in the region of 50%. Chemotherapy makes a limited contribution to tumour control.

Very substantial numbers of patients with common of cancers achieve long-term tumour control largely by the use of radiation therapy. Informed debate on the funding of national cancer programs requires data on the relative roles of the main treatment modalities. Broad estimates by De Vita et al. (1979) and Souhami and Tobias (1986) suggested that local treatment, which includes surgery and/or radiotherapy, could be expected to be successful in approximately 40% of these cases; in perhaps 15% of all cancers, radiotherapy would be the principal form of treatment. By contrast, many patients do receive chemotherapy but their contribution to the overall cure rate of cancer may be only around 2%, with some prolongation of life in perhaps another 10%. This is because the diseases in which chemotherapy does well are rare. If these figures are correct, it may be that around seven times as many patients currently are cured by radiotherapy as by chemotherapy. This is not to undervalue the important benefits of chemotherapy in a number of chemosensitive diseases, but to stress the greater role of radiotherapy as a curative agent (Tubiana, 1992).

Considerable efforts are being devoted at the present time to the improvement of radiotherapy and chemotherapy. Wide publicity is given to the newer areas of drug development such as lymphokines, growth factors, anti-oncogenes and gene therapy. But if we were to imagine aiming to increase the cure rate of cancer by, say, 2%, it would seem on a realistic estimation that this would more likely be achieved by increasing the results of radiotherapy from, say, 15% to 17% than by doubling the results achieved by chemotherapy.

There are three main ways in which such an improvement in radiotherapy might be obtained:

1 by raising the standards of radiation dose prescription and delivery to those currently in use in the best radiotherapy centres;

2 by improving radiation dose distributions beyond those that are conventionally achieved, either using techniques of conformal radiotherapy with photons, or ultimately by the use of proton beams;

3 by exploiting radiobiological initiatives

The proportion of radiotherapists world-wide who work in academic centres is probably less than 5%. They are the clinicians who may have access to large new treatment machines, for instance for proton therapy, or to new radiosensitizers or to new agents for targeted therapy. Chapters of this book allude to these exciting developments which may well have an impact on treatment success in the future. But it should not be thought that the improvement of radiation therapy lies exclusively with clinical research in the specialist academic centres. It has widely been recognized that by far the most effective way of improving cure rates on a national or international scale is by quality assurance in the prescription and delivery of a radiation treatment. Chapters 12-14 of this book deal with the principles on which fractionating schedules should be optimized, including how to respond to unavoidable gaps in treatment. For many radiotherapists this will be the most important part of this book, for in even the smallest department it is possible, without access to greatly increased funding, to move closer to optimum fractionating practices.


1.2 THE ROLE OF RADIATION BIOLOGY

Experimental and theoretical studies in radiation biology contribute to the development of radiotherapy at three different levels, moving in turn from the most general to the more specific:

Ideas: providing a conceptual basis for radiotherapy, identifying mechanisms and processes that underlie the response of tumours and normal tissues to irradiation and which help to explain observed phenomena. Examples are knowledge about hypoxia, reoxygenation, tumour cell repopulation or mechanisms of repair of DNA damage.

Treatment strategy: development of specific new approaches in radiotherapy. Examples are hypoxic cell sensitizing, high-LET radiotherapy, accelerated radiotherapy, hyperfractionation.

Protocols: advice on the choice of schedules for clinical radiotherapy, for instance conversion formulae for changes in fractionating or dose rate, or advice on whether to use chemotherapy currently or sequentially with radiation. We may also include under this heading methods for predicting the best treatment for the individual of patient (individualized radiotherapy).

There is no doubt that radiobiology has been very fruitful in the generation of new ideas and in the identification of potentially exploitable mechanisms. A variety of new treatment strategies have been produced, but unfortunately few of these have so far led to demonstrable clinical gains with regard to the third an of the levels listed above) the newer conversion formulae based on the linear-quadratic equation seem to be successful. But beyond this, the ability of laboratory the science to guide the radiotherapist in the choice of specific protocols is limited by the inadequacy of the theoretical and experimental models: it will always be by necessary to rely on clinical trials for the final choice of a protocol.


1.3 THE TIME-SCALE OF EFFECTS IN RADIATION BIOLOGY

Irradiation of any biological system generates a succession of processes that differ enormously in time-scale. This is illustrated in Figure 1.1 where these processes are divided into three phases (Boag, 1975).

The physical phase consists of interactions between charged particles and the atoms of which the tissue is composed. A high-speed electron takes about 10-18 seconds to traverse the DNA molecule and about 10-14 seconds to pass across a mammalian cell. As it does so, it interacts mainly with orbital electrons, ejecting some of them from atoms (ionization) and raising others to higher energy levels within an atom or molecule (excitation). If sufficiently energetic, these secondary electrons may excite or ionize other atoms near which they pass, giving rise to a cascade of ionization events. For 1 Gy of absorbed radiation dose, there are in excess of 105 ionizations within the volume to of every cell of diameter 10 micron.

The chemical phase describes the period in which these damaged atoms and molecules react with other to cellular components in rapid chemical reactions. Ionization and excitation lead to a breakage of chemical bonds and the formation of broken molecules, known as free radicals. These are highly reactive and they engage in a succession of reactions that lead eventually to the restoration of electronic charge equilibrium. Free-radical reactions are complete within approximately 1 ms of radiation exposure. An important characteristic of the chemical phase is the competition between scavenging reactions, for instance with sulphydryl compounds that inactivate the free radicals, and fixation reactions that lead to stable chemical changes in biologically important molecules.

The biological phase includes all subsequent processes. These begin with enzymatic reactions that act on the residual chemical damagers: vast majority of lesions, for instance in DNA, are successfully repaired. Some rare lesions fail to repair and it is these that lead eventually to cell death. Cells take time to die; indeed, after small doses of radiation they may undergo a number of mitotic divisions before dying.

It is the killing of stem cells and the subsequent loss of the cells that they would have given rise to that causes the early manifestations of normal-tissue damage during the first weeks and months after radiation exposure. Examples are breakdown of the skin or mucosa, denudation of the intestine and haemopoietic damage (see Section 4.4). A secondary effect of cell killing is compensatory cell proliferation, which occurs both in normal tissues and in tumours. At later times after the irradiation of normal tissues the so-called late reactions appear. These include fibrosis and telangiectasia of the skin, spinal-cord damage and blood-vessel damage. An even later manifestation of radiation damage is the appearance of second tumours (i.e. radiation carcinogenesis). The time-scale of the observable effects of ionizing radiation may thus extend up to many years after exposure.

1.4 RESPONSE OF NORMAL AND MALIGNANT TISSUES TO RADIATION EXPOSURE.

Much of the text of this book focuses on effects high of radiation exposure that become apparent to the clinician or the patient during the weeks, months and years after radiotherapy. These effects are seen both in tumour tissues and in the normal tissues that surround a tumour and which are unavoidably exposed to radiation. The primary tasks of radiation biology as applied to radiotherapy are to explain observed phenomena, and to suggest improvements to existing therapies (as set out in Section 1.2).

The response of a tumour is seen by regression, often followed by regrowth (or recurrence), but perhaps with failure to regrow during the normal lifespan of the patient (which we term cure or local control). These italicized terms describe the tumour responses that we seek to understand. The relationship between regression and regrowth is illustrated graphically in Figure 2.6. The cellular basis of tumour response, including tumour control, is dealt with in Section 6.6.

The responses of normal tissues to therapeutic radiation exposure range from those that cause mild discomfort to others that are life threatening. The speed at which a response develops varies widely from one tissue to another and often depends on the dose of radiation that the tissue receives. Generally speaking, the haemopoietic and epithelial tissues manifest radiation damage within weeks of radiation exposure, whereas damage to connective tissues becomes important at later times. A major development in the radiobiology of normal tissues during the 1980s was the realization that early and late normal-tissue responses are differently modified by a change in dose fractionating and this has given rise to the current interest in hyperfractionation (Section 14.3).

The first task of a radiobiologist is to measure a tissue response accurately and reliably. The term assay is used to describe such a system of measurement. Assays for tumour response are described in Section 17.3. For normal tissues, the following three general types of assay are available.

Scoring of gross tissue effects. It is possible to grade the severity of damage to a tissue using an arbitrary scale as is done in Figure 4.1 or Figure 11.2. In superficial tissues this approach has been remarkably successful in allowing isoeffect relationships to be determined.

Assays of tissue function. For certain tissues, functional assays are available that allow radiation effects to be documented. Examples are the use of breathing rate as a measure of lung function in mice (see Figure 4.5), EDTA clearance as a measure of kidney damage (see Figure 12.4), or blood counts as an indicator of bone marrow function.

Clonogenic assays. In some tumours and some normal tissues it has been possible to develop methods by which the colony of cells that derives from a single irradiated cell can be observed. In tumours this is particularly important because of the fact that regrowth of a tumour after suppurative treatment is caused by the proliferation of a small number of tumour cells that retain colony forming ability. This important area of radiation-biology is introduced in Chapter 6.

1.5 RESPONSE CURVES, DOSE-RESPONSE CURVES AND ISOEFFECT RELATIONSHIPS.

The damage that is observed in an irradiated tissue increases, reaches a peak and then may decline (Figure l.2A). How should we quantify the magnitude of this response? We could use the measured response at some chosen time after irradiation, such as the time of maximum response, but the timing of the peak may change with radiation dose and this would lead to some uncertainty in the interpretation of the results. A common device is to calculate the cumulative response by integrating this curve from left to right (Figure 1.2B). Some normal-tisuses responses give a cumulative curve that rises to a plateau, and the height of the plateau is a good measure of the total effect of that dose of radiation on the tissue. Other normal-tissue, in particular the late responses seen in connective and vascular tissues, are progressive and the cumulative response curve will continue to rise (Figures 11.3 and 11.4). The quantification of clinical late reactions is dealt with in section 11.4.

The next stage in a study of the radiation response of a tissue will be to vary the radiation dose and thus to investigate the dose-response relationship (Figure 1.2C). Many examples of such curves are given in this book, for instance Figures 5.4, 10.6 and 11.6. Cell survival curves (see section 6.3) are further examples of dose-response curves that are widely used in radiobiology. The position of the curve on the dose scale indicates the sensitivity of the tissue to radiation; its steepness also gives a direct indication of the change in response that will accompany an increase or decrease in radiation dose. These aspects of dose-response curves are dealt with in detail in Chapter 10.

The foregoing paragraphs have for simplicity referred to dose as though we are concerned only with single radiation exposures. It is a well-established fact that multiple radiation doses given over a period five of few weeks give a better curative response than can be achieved with a single dose. Diagrams similar to Figures 1.2A, 1.2B and etc can also be constructed for fractionally radiation treatment, although the results are easiest to interpret when the fractions are given over a time that is short compared with the time-scale of development of the response. If we change the schedule of dose fractionating, for instance by giving a different number of fractions, changing the fraction size or the radiation dose rate, we can then investigate the therapeutic effect in terms of an isoeffect plot (Figure 1.2D). Experimentally this is done by per forming multiple studies at different doses for each chosen schedule and calculating a dose-response curve. We then select some particular level of effect (T in Figure 1.2C) and read off the total radiation dose that gives this effect. For effects on normal tissues the isoeffect will often be some upper limit of tolerances of the tissue perhaps expressed as a probability of tissue failure (sections 5.1 and 10.1).The isoeffect plot shows how the total radiation dose for the chosen level of effect varies with dose schedule. Examples are Figures gore 12.3 and 14.3, and recommendations for tolerance calculations are set out in chapters 12 and 13. The dashed line in Figure 1.2D illustrates how therapeutic conclusions may be drawn from isoeffect curves. lf the curve for tumour response is flatter than for normal-tissue tolerance, then there is a therapeutic advantage in using large fraction numbers: a tolerance dose given using small fraction numbers will be far short of the tumour-effective dose, whereas for large fraction numbers it may be closer to an effective dose.


1.6 THE CONCEPT OF THERAPEUTIC INDEX

Discussion of the possible benefit of a change in treatment strategy must always consider simultaneously the effects on tumour response and on normal- tissue damage. A wide range of factors enter into this assessment. In the clinic, in addition to quantifiable aspects of tumour response and toxicity there may be a range of poorly quantifiable factors such as new forms of toxicity or risks to the patient, or practicability and convenience to hospital staff, also cost implications. These must be balanced in the clinical setting. The function of radiation biology is to address the quantifiable biological aspects Of a change in treatment.

In the laboratory this can be done by considering dose-response curves. As radiation dose is increased, there will be a tendency for tumour response to increase, and the same is also true of normal-tissue damage. If, for instance, we measure tumour response by determining the proportion of tumours that are controlled, then we expect a sigmoid relationship to dose (for fractionally radiation treatment we could consider the total dose or any other measure of treatment intensity). This is illustrated in the upper part of Figure 1.3. If we quantify normal-tissue damage in some way for the same treatment schedule, there will also be a rising curve of toxicity (lower panel). The shape of this curve is unlikely to be the same as that for tumour response and we probably will not wish to determine more than the initial part of this curve since a high frequency of severe damage is unacceptable. By analogy with that must be done in the clinic, we can then fix a notional upper limit of tolerance (see Section 5.1). This fixes, for that treatment schedule, the upper limit of radiation dose that can be tolerated, for which the tumour response is indicated by the point in Figure 1.3 labelled A.

Consider now the effect of adding treatment with a cytotoxic drug. We expect that this will be seen as a movement to the left of the curve tumour control (Figure l.3). There will probably also be an increase in damage to normal tissues, which will consist of a leftward movement of the toxicity curve. The relative displacement of the curves for the tumour and normal tissues will usually be different and this fact makes the amount of benefit very difficult to assess. How do we know whether there has been a real therapeutic gain? For studies on laboratory animals, there is a straightforward way of asking whether the combined treatment is better than radiation alone: for the same tolerance level of normal-tissue damage (the broken line), the maximum radiation dose (with drug) will be lower and the corresponding level of tumour control is indicated by point B in the figure. If B is higher than A, then the combination is better than radiation alone for it gives a greater level of tumour control for the same level of morbidity.

This example indicates the radiobiological concept of therapeutic index: it is the tumour response for a fixed level of normal-tissue damage (see Section 10.6). The term therapeutic window describes the (possible) difference between the tumour control dose and the tolerance dose. The concept can in principle be applied to any therapeutic situation or to any appropriate measures of tumour response or toxicity. Its application in the clinic is, however, not a straightforward a matter, as indicated in Section 20.1. Therapeutic index carries the notion of cost-benefit analysis. It is impossible to reliably discuss the potential benefit of a new treatment without reference to its effect on therapeutic index.


1.7 THE IMPORTANCE OF RADIATION BIOLOGY FOR THE FUTURE DEVELOPMENT OF RADIOTHERAPY

Many developments in radiotherapy have resulted from new technologies or have been made empirically by clinicians; there are few examples of developments that have begun in the radiobiological laboratory and been carried through to the point where patient survival has significantly improved. The role of oxygen is one positive example that has led to benefits (see Chapter 16), also the clinical gains obtained with accelerated fractionating and hyperfractionation (see Chapter 14).

Compared with chemotherapeutic drugs, radiation is now a well understood cytotoxic agent. Its access to tumour cells is just a matter of dosimetry, independent of the transport mechanisms that largely determine the effectiveness of chemical agents. The sequence of processes listed in Section 1.2 above are well described for radiation; some of them are equally relevant to the response of tissues to cytotoxic drug treatment, and thus research into radiation biology has brought benefits to other areas of therapeutic cancer research.

The future is likely to require greater and greater dependence on basic science. The simple empirical things have mostly been fully exploited and increasing knowledge about the cellular and molecular nature of radiation effects will undoubtedly lead to developments for which the radiotherapist will require grounding in fundamental mechanisms. That is the purpose of this book.