Mini-reviewAbscopal effects of radiation therapy: A clinical review for the radiobiologist
Introduction
The systemic effects of localized radiation are well-recognized phenomena. In routine clinical practice, generalized fatigue, anorexia and weight loss are commonplace effects of localized therapeutic irradiation. A rarer clinical response to radiation therapy is tumor regression at sites distant to the irradiated volume, commonly known as the abscopal effect. The term ‘abscopal’ was defined by Mole in 1953 as a tumor event occurring “at a distance from the irradiated volume but within the same organism” [1]. The etymology of the word is Latin, with the prefix ‘ab’ denoting “position away from” and ‘scopus’ as a target for shooting at. In that paper, Mole posed fundamental questions such as “How much of this abscopal effect occurs and how is it produced?”. Over 50 years later the answers to these questions remain to be fully elucidated. A broader definition of the term abscopal was given by Andrews as “…local irradiation of one tissue involved in a response in another or similar tissue remote from the irradiated site” [2], a concept that encompasses both distant tumor and distant normal tissue effects. The purpose of this review is to investigate known clinical cases of abscopal responses and to discuss potential mechanisms. Clinical cases encompassing both abscopal tumor response, and normal tissue effects, will be reviewed. As the mechanism of effect in lymphoma and leukaemia are likely to be dramatically different from that in non-haematological malignancies, this paper will focus on the abscopal effects in the latter.
Section snippets
Spontaneous regression of cancer and the abscopal effect
The history of spontaneous regression of tumors is fascinating, with Boyd [3], and then Everson and Cole [4] both publishing monographs on the topic in 1966. Boyd suggested that tumors that regressed spontaneously could be termed Saint Peregrine tumors, after the young priest with a large bone tumor who avoided amputation, allegedly through intense prayer. He died in 1345 aged 80 without recurrence of the tumor. In an annotated biography published in 1993 of several hundred cases of reported
Systemic effects of radiation in normal tissues
Radiation therapy inevitably involves exposure of normal tissues surrounding the tumor to ionising radiation. The majority of adverse effects of radiation therapy on normal tissues can be attributed predominantly to depletion of cell populations through direct cell killing and/or inhibition of repopulation in rapidly renewing tissues such as gut or skin; these effects are organ-specific [24], [25]. In addition to these direct actions of irradiation, the presence of tumor itself can contribute
Effect of dose and fractionation
The full immunotherapeutic potential of radiotherapy may be influenced by the dose and fractionation of radiation employed, for both single fraction and fractionated approaches [53]. Conventional fractionation in the clinical setting typically employs daily fractions of 1.8 Gy–2 Gy during treatment. As lymphocytes are exquisitely sensitive to irradiation, repetitive daily delivery of cytotoxic doses of radiation can deplete migrating immune effector cells. However, work from our institution
Mechanisms of the abscopal effect
There are numerous reports of induction of radiation-related abscopal effects in animal models, with two major streams of research: (1) disappearance of a tumor or a delay of tumor growth as an end-point (reviewed in [62], [66], [67]), and (2) induction of genomic instability and epigenetic changes in non-targeted organs and tissues after a radiation exposure of a part of the body (reviewed in [52], [68], [69], [70]; also see review by Sprung et al. in this issue of Cancer Letters). Animal
Implications for current clinical practice and future therapies
The abscopal effect is often considered a medical curiosity, and a unifying model of its mechanisms has yet to be established. Further confusing the matter is the probable difference in the mechanism of effect in haematological versus non-haematological malignancies. It is likely that in lymphomas and leukaemias, a simpler mechanistic model comprising reduction of circulating populations of lymphocytes can account for at least some clinically demonstrated ‘pseudo-abscopal’ effects. In
Conclusions
Radiation therapy for cancer is usually considered to be simply a local treatment modality, however, there is clinical evidence of longer-range effects that render this conceptual simplicity misleading. It is clear that abscopal effects may be both beneficial in terms of tumor control and harmful in terms of normal tissue toxicity. The mechanisms of these effects are multifactorial and complex in nature. There is a pressing need for our current understanding of the systemic effects of localized
Conflict of interest
No author has any conflict of interest to declare.
Acknowledgements
This work was partly supported by the Australian National Health and Medical Research Council (NHMRC) Grant 10275598. Dr. Shankar Siva is partly supported by the NHMRC scholarship 1038399.
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