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Peggy Olive from the British Columbia Cancer Research Center in Canada is credited with the development of a method to measure DNA damage in individual cells based on the technique of microelectrophoresis that she named the 'comet assay'; a well-accepted method to measure DNA damage, hypoxia and apoptosis. A multifaceted person and an ardent campaigner of environmental issues, Peggy has contributed significantly to several areas of radiobiology related to the treatment of cancer, her expertise being tumor hypoxia and gamma H2AX foci as a biomarker in radiotherapy.

Purpose: Review the historical basis for the use of fractionated radiation in radiation oncology., Conclusion: The history of dose fractionation in radiation oncology is long and tortuous, and the radiobiologist's understanding of why fractionation worked came decades after radiation oncologists had adopted multi-week daily-dose fractionation as 'standard'. Central to the history is the search for 'isoeffective' formulas that would allow different radiation schedules to be compared. Initially, this meant dealing with different lengths of treatment, leading to the 1944 Strandqvist formulation that dominated thinking for decades. Concerns about the number of fractions, not just the total time, led to the 1967 Ellis NSD formulation that held sway through the 1980s. The development of experimental radiotherapy in 1970s (e.g. Fowler's work at the Gray Laboratory, and Fischer's work at Yale) led to biologically-based approaches that culminated with the Biologically Effective Dose (BED) concept. BED is the current dogma for treatment optimization, but it must be used with caution, as there are multiple formulations, and some parameters have debatable values. There is also a controversy about whether BED is biologically-based or a 'curve-fitting' exercise. These latter issues are beyond the scope of this article, but the history of fractionation models suggests that our current concepts are probably wrong, although when used with caution they are clearly useful.

Hanahan and Weinberg recently updated their conceptual framework of the "Hallmarks of Cancer". The original article, published in 2000, is among the most highly cited reviews in the field of oncology. The goal of this review is to highlight important discoveries in radiation biology that pertain to the Hallmarks. We identified early studies that exemplified how ionizing radiation affects the hallmarks or how radiation was used experimentally to advance the understanding of key hallmarks. A literature search was performed to obtain relevant primary research, and topics were assigned to a particular hallmark to allow an organized, chronological account of the radiobiological advancements. The hallmarks are reviewed in an order that flows from cellular to microenvironmental effects.

The authors have reviewed some of the most important and established factors that determine the effectiveness of IR in a wide variety of tumor types and normal tissues: the significance of increasing the dose of radiation, the importance of altered fractionation schemes, such as accelerated fractionation or hyperfractionation, and the need to address tumor hypoxia. Therapeutic gain can only be achieved when the increased tumor toxicity produced by these treatment modifications is balanced against injury to early-responding as well as late-responding normal tissues. In the not too distant future, therapeutic gain may be maximized by individualized therapies that are based on phenotypic and genotypic profiling of tumors and patients. For example, predicting which tumors respond to IR with accelerated tumor cell repopulation will allow us to apply more intense accelerated treatment regimens, while subjecting patients with slowly proliferating tumors to less toxic therapies. Similarly, the combination of radiation therapy with molecularly targeted pharmacologic agents will be a highly individualized treatment approach. However, to some degree, radiation therapy will always have to remain unselective and indiscriminant to inactivate the last surviving dormant and probably drug-resistant tumor clonogen. Although the field of radiation biology is rapidly evolving as a result of advances in molecular biology and genetics and the availability of new technologies, a thorough understanding of the established factors that determine radiation responses will remain an important prerequisite for the successful application of multimodal cancer therapies and molecularly targeted approaches in the future.

Over the twentieth century the discipline of radiation oncology has developed from an experimental application of X-rays to a highly sophisticated treatment of cancer. Experts from many disciplines - chiefly clinicians, physicists and biologists - have contributed to these advances. Whereas the emphasis in the past was on refining techniques to ensure the accurate delivery of radiation, the future of radiation oncology lies in exploiting the genetics or the microenvironment of the tumour to turn cancer from an acute disease to a chronic disease that can be treated effectively with radiation.

Claudius Regaud can be regarded as the founding father of both radiobiology and radiotherapy. His research extended widely in oncology and the conclusions which he drew from his work are considered in the light of our modern practice of the clinical science of radiation therapy.

The treatment of cancer using fast neutrons was first attempted from 1938 to 1942, only a few years after the identification of the particle in 1932. The radiobiological information which was available at that time was both inadequate and contradictory, and provided no definite rationale for using neutrons in preference to X-rays. The doses given were often too high, causing many patients to suffer severe late reactions. As a result, further attempts to use fast neutrons in radiotherapy were abandoned for nearly 30 years. Interest in the use of fast neutrons was stimulated again by the elucidation of the oxygen effect and the discovery that it was less for neutrons than for X-rays. Thus tumours containing hypoxic cells would be less protected against neutrons. Also the reduced repair of sublethal damage with neutrons provided at least a partial explanation of the miscalculation of dose in the early trial. This was confirmed by means of a series of experiments on pig skin, from which it was also concluded that late damage was not more severe after neutrons, compared with X-rays for a given degree of early damage. A new clinical trial began in 1966, and the results so far are encouraging. In order to relate radiotherapy experience with X-rays to neutrons, it is necessary to measure the relative biological effectiveness (RBE) of neutrons. This has been done for skin of man, pig, mouse and rat. Because of the smaller recovery from sublethal damage after neutrons, the RBE increases as the dose per fraction decreases, but the relationship between RBE and dose per fraction is the same for all four species. Similar information, but only for rodents, has been obtained for a variety of other normal tissues with both cyclotron-produced and monoenergetic 14 or 15 meV neutrons. Experiments with animal tumours have indicated that there might be a wide variation in RBE from tumour to tumour due both to the presence of hypoxic cells and to differences in their capacities to recover from sublethal damage after X-rays and neutrons. The largest series of experiments on one tumour shows that whereas certain fractionation techniques with X-rays may produce a poor tumour response for a given level of normal tissue damage, all the neutron regimes produced a similar, close to optimum result. There is no evidence from which to expect any special dangers from neutron irradiation, and their likely advantage is that they may provide a more reliable method of radiotherapy as well as sterilizing some tumours which are normally resistant to X-rays.