Abscopal effect of local hyperthermia

Bystander effect (abscopal effect) means that a local tumor treatment can affect the behavior of the far distant metastases. It was first discovered by radiooncologists and remained a higly controversial topic until recent years [1, 2]. Intensive research is conducting to reveal the immunbiological basis [3–5] and mechanism of action of this effect [6] and using the benefits in the regular oncological practice.

Bystander effect: novel prospect in Oncothermia 

The word abscopal is derived from Latin ab means “position away from” and “scopos meaning” a target for shooting at. In both radiotherapy patients and in external-beam-irradiated animal models, most reports on abscopal effects refer to antitumor consequences outside the radiation field. Much of the observed physiological abscopal effect has been associated with splenic irradiation [7]. In the clinical setting, these include regression of hepatocellular carcinomas after radiotherapy to treat a tumor at the base of the spine and histologic changes in metastatic lymph nodes in some women treated for breast cancer but also in variety of malignancies including lymphoma, papillary adenocarcinoma, melanoma, adenocarcinoma of the esophagus, chronic lymphocytic leukemia [8-14]..These bystander effects take place in the neighbors of irradiated cells or in other non-irradiated cells that have received secreted signals from the irradiated cells. As such, bystander effects are somehow communicated from an irradiated cell to a non-irradiated bystander cell via cell-to cell gap junctions (14) or by the secretion on shedding of soluble factors [15-17].

Two theories about local hyperthermia effects

There have been two main theories proposed to explain the abscopal antitumor effect. The first applies to leukemias and lymphomas, it is hypothesized that during splenic irradiation diseased lymphocytes circulate through the irradiated volume (spleen), and as the splenic size decreases the remotely located masses also decrease in size, giving an impression of a systemic antitumor effect from local treatment. The second applies to solid tumors, it is postulated that local radiation induces a release of mitotic inhibitors (cytokines) into the circulation that mediate a systemic antitumor effect. It has been demonstrated that an elevation of circulating tumor necrosis factor after radiotherapy that coincided with the regression of a hepatocellular carcinoma situated away from the radiation field [13]. Others proposed hypothesis is that the abscopal effect is mediated by the immune system. Irradiation of tumor in one site induces release of circulating tumor antigen or inflammatory factors that may then mediate an augmented immune response against non-irradiated, malignant lesions expressing similar tumor antigens [14-22]. Basing on the published literature abscopal effects could be observed in patients treated with radiotherapy, radiotherapy plus oncothermia or only oncothermia [23,24].

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  8. Rees GJ. Abscopal regression in lymphoma: a mechanism in common with total body irradiation? Clin. Radiol. 1981;32:475–480.
  9. Ehlers G, Fridman M. Abscopal effect of radiation in papillary adenocarcinoma. Br J Radiol. 1973;46:220–222.
  10. Kingsley D. An interesting case of possible abscopal effect in malignant melanoma. Br J Radiol. 1975;48:863–866.
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  12. Sham R. The abscopal effect and chronic lymphocytic leukemia. Am J Med. 1995;98:307–308. doi: 10.1016/S0002-9343(99)80380-5.
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  14. Jolles B, Harrison RG. Radiation skin reaction and depletion and restoration of body immune response. Nature (Lond.) 1963;198:1216–1217.
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  16. Porter DL, Levine BL, Kalos M, Bagg A, June CH, (2011) Chimeric Antigen Receptor–Modified T Cells in Chronic Lymphoid Leukemia N Engl J Med; 365:725-733
  17. Trott KR. Non-targeted radiation effects in radiotherapy-roles of radiation-induced genomic instability and of the bystander effect in cancer cure by radiotherapy. Acta Oncologia. 2001;40:976–980.
  18. Hartford A, Gohongi T, Fukumura D, Jain R. Irradiation of a primary tumor, unlike surgical removal, enhances angiogenesis suppression at a distal site: potential role of host-tumor interaction. Cancer Res. 2000;60:2128–2131.
  19. Uchida A, Mizutani Y, Nagamuta M, Ikenaga M. Elevation of sensitivity of tumor cells and lytic function of NK cells. Immunopharmacol. Immunotoxicol. 1989;11:507–519.
  20. Formenti SC, Demaria S. Systemic effects of local therapy. Lancet Oncol. 2009; 10: 718-726.
  21. Zahidunnabi M, et.al:, (2009) Fractionated but Not Single-Dose Radiotherapy Induces an Immune-Mediated Abscopal Effect when Combined with Anti–CTLA-4 Antibody. Clin Cancer Res 2009;15(17)
  22. G. Andocs, N. Meggyeshazi, Y. Okamoto, L. Balogh, and O. Szasz, “Bystander Effect of Oncothermia,” Conference Papers in Medicine, vol. 2013, Article ID 953482, 6 pages, 2013. doi:10.1155/2013/953482
  23. G Fiorentini, S M Yoon, Okamoto Yan et al., Abscopal effect: new perspectives in Oncothermia, Oncothermia Journal, June 2013