British Journal of Radiology

Clinical gains have been reported from the use of nonstandard fractionation schedules planned with a radiobiological basis. Hyperfractionation provides the leading example, as described below, with accelerated fractionation being developed more recently. Although examples of almost every kind of fractionated schedule can be found in the literature over the past 90 years, it is only within the last decade that the biological factors concerning overall time and delayed proliferation after irradiation, and the effect of dose per fraction, have been understood. Both these factors operate differently on late- and early-reacting tissues, because cell proliferation in late-reacting tissues is slow or absent, but early reacting tissues and tumours depend upon cells that proliferate rapidly. This basic knowledge is still diffusing through the radiotherapy community and I hope this review will help the diffusion process. The biological factors concerning fractionation seem to apply to the majority of tissues and tumours, so that new schedules can be planned that are effective in practice.

Attempts to deal with hypoxic cells in tumours or to use high-linear-energy-transfer (LET) radiation have been less generally successful, probably because in those strategies we need to identify subpopulations that are smaller. Tumours that are resistant to conventional radiotherapy because they contain hypoxic cells and do not reoxygenate cannot be identifed yet.

The association between the low dose of ionizing radiation received by the fetus in utero from diagnostic radiography, particularly in the last trimester of pregnancy, and the subsequent risk of cancer in childhood provides direct evidence against the existence of a threshold dose below which no excess risk arises, and has led to changes in medical practice. Initially reported in 1956, a consistent association has been found in many case-control studies in different countries. The excess relative risk obtained from combining the results of these studies has high statistical significance and suggests that, in the past, a radiographic examination of the abdomen of a pregnant woman produced a proportional increase in risk of about 40%. A corresponding causal relationship is not universally accepted and this interpretation has been challenged on four grounds. On review, the evidence against bias and confounding as alternative explanations for the association is strong. Scrutiny of the objections to causality suggests that they are not, or may not be, valid. A causal explanation is supported by evidence indicating an appropriate dose-response relationship and by animal experiments. It is concluded that radiation doses of the order of 10 mGy received by the fetus in utero produce a consequent increase in the risk of childhood cancer. The excess absolute risk coefficient at this level of exposure is approximately 6% per gray, although the exact value of this risk coefficient remains uncertain.

The prevalence, validity and reliability of high-intensity zones in the annulus fibrosus seen on T  2-weighted magnetic resonance images of patients with intractable low-back pain were determined. This sign was readily recognized by two independent observers. It occurred in 28% of 500 patients undergoing magnetic resonance imaging for back pain. The presence of a highintensity zone correlated significantly with the presence of Grade 4 annular disruption and with reproduction of the patient's pain. Its sensitivity as a sign of either annular disruption or pain was modest but its specificity was high, and its positive predictive value for a severely disrupted, symptomatic disc was 86%. This sign is diagnostic of painful internal disc disruption.

CT has recently been used in mass screening for lung cancer. Small cancers have been identified but the growth characteristics of these lesions are not fully understood. We identified 82 primary cancers in our 3-year mass CT screening programme, of which 61 were examined in the present study. The volume doubling time (VDT) was calculated based on the exponential model using successive annual CT images or follow-up CT images. All cases were also examined in the hospital by high resolution CT (HRCT). Lesions were divided into three types based on HRCT characteristics: type G (n = 19), ground glass opacity (GGO); type GS (n = 19), focal GGO with a solid central component; and type S (n = 23), solid nodule. 18 (95%) lesions of type G, 18 (95%) of type GS and 7 (30%) of type S were invisible on conventional chest radiographs. The mean size of the tumour was 10 mm, 11 mm and 16 mm for type G, type GS and type S, respectively. Most tumours (80%) were adenocarcinomas; 78% of these were GGO (type G and GS). Mean VDT values were 813 days, 457 days and 149 days for type G, type GS and type S, respectively; these are significantly different from each other (p < 0.05). Our results show that annual mass screening CT for 3 successive years resulted in the identification of a large number of slowly growing adenocarcinomas that were not visible on chest radiographs.

A body of evidence that vascular-mediated damage occurs in murine tumours after many existing forms of anti-tumour therapy is rapidly accumulating (see Gray Conference Proceedings edited by Moore & West, 1991). Rapid conventional screens of cells in vitro or using leukaemias of lymphomas will not detect this mode of action and such screens will therefore miss effective agents. A change in the approach to experimental cancer therapy is needed to ensure that this important new avenue is fully investigated. Solid tumours will need to be studied and the importance of specific tumour cell biochemistry (e.g. on tissue factor procoagulant activity), of endothelial status and the immunocompetence of the host are all likely to be important. It is a subject of considerable debate at present whether transplanted subcutaneous mouse tumours are adequate models and whether they will reflect the response of spontaneous tumours, or even of transplants into other sites. Xenografts are not likely to be appropriate if the immuno-suppressed hosts lack the cells needed for the cytokine component of the pathway.

The strategy of design and screening of new agents, for scheduling of existing agents and particularly the sequencing of adjunctive therapies are likely to be completely different for the “direct” tumour cell or “indirect” vascular-mediated approaches. It may eventually be appropriate to combine vascular manipulation with direct cytotoxicity aimed at malignant cells but the two mechanisms must be recognized as distinct entities and considered separately before attempting to coordinate them. It is important therefore to identify the “hallmarks” of vascular mediated injury and the means by which this can be distinguished from direct cell kill. These may be detectable in the tumour response but clues can also be gained from the side effects that are seen in normal tissues both with existing and with novel therapies (Figure 7).

The appeal of vascular-mediated ischaemic therapy is that it is systemic and will have the potential of being effective on any tumour with a newly evoked vascular network, i.e. of about 1 mm in diameter, but it will be even more effective on large tumours than on small. Thus it should affect both large primary tumours and disseminated small metastases. The studies with many different anti-cancer agents have illustrated the potential complexity of responses that can appear to cause tumour cell death by collapse or occlusion of the blood supply. They have also focused attention on features of disparate agents, e.g. TNF, FAA, PDT, which may share similar pathways.

No single feature of neovasculature can be high-lighted as the sole route by which such antivascular therapy should be targeted. Rapid proliferation of the endothelial cells may prove to be a target, but it also influences differentiation characteristics, so that the immature cells will function abnormally. The permeability of these poorly formed vessels may lead to extravasation of proteins leading to increased interstitial pressures and by this means to an imbalance between intravascular and extravascular pressures and hence to collapse of the thin-walled vessels. Changes in systemic blood pressure, cardiac output, viscosity or coagulation and especially a redistribution of regional perfusion would all have differential effects in tumours and normal vessels. Clearly both vascular patho-physiology and the complexity of endothelial cell function and its imbalance in neovasculature will be important in understanding the mechanism of action of antivascular strategies. This very challenging boundary between oncology and a number of other medical and biological fields promises to lead to altered attitudes to existing therapies and the discovery of completely new classes of anti-cancer agents. The next decade should translate into clinical benefit for patients if the progress in this field continues to be as rapid as it has been in the late eighties. We must now determine what characteristics make one tumour more sensitive than another to agents such as heat, PDT, cytokines and FAA, and learn how to extrapolate from those rodent tumours to the human.