Advertisement

Journal of Radiation Oncology

, Volume 8, Issue 2, pp 143–156 | Cite as

The systemic immunostimulatory effects of radiation therapy producing overall tumor control through the abscopal effect

  • Mark A. D’Andrea
  • G. Kesava ReddyEmail author
Article
  • 21 Downloads

Abstract

Objective

Emerging studies show that radiation therapy produces an important out of field (distant) effect known as the ‘‘abscopal effect” in nonirradiated tumor sites. The objective of this study was to provide an overview of the current state of knowledge and clinical experience of radiation therapy producing abscopal effects in the management of different types of malignant diseases.

Methods

Peer-reviewed published clinical evidence on the abscopal effect of radiation therapy was collected using electronic databases such as Medline via PubMed and Google Scholar. The reference lists were searched in the publications that we obtained in an attempt to find additional relevant publications. Non-indexed peer-reviewed journals were manually searched and relevant information was extracted. The search was restricted to English language articles. The clinical data on the abscopal effect of radiation therapy were reviewed and the outcomes have been summarized.

Results

Currently, only clinical case reports and anecdotes have slowly converted into solid clinical data and interest is building in the field of radiation therapy, specifically on how local radiation can produce the abscopal effects for the management of different types of malignant tumors. Extensive clinical evidence suggests that the radiation therapy induced abscopal antitumor effects are mediated by immune cells such as the T-lymphocytes. This forms a basis for using radiation therapy in combination with immunotherapy to augment the abscopal response rates in cancer patients. Current evidence demonstrates that radiation therapy induces abscopal responses across many tumor types.

Conclusion

Together, the clinical outcomes from published reports suggest that localized radiation therapy is capable of inducing abscopal effects in a wide variety of malignant tumors. With the advent of novel immunotherapies, the potential for immune activation by radiation defines a novel role for radiation therapy in the treatment of systemic disease. A clinical consideration of the abscopal effects produced by radiation therapy could lead to a revolutionary change in the current management of patients including radiation treatment strategies and immunotherapies for various malignant tumors.

Keywords

Abscopal effect Immunomodulation Malignant tumors Metastasis Radiation therapy Solid tumors Systemic effects 

Notes

Compliance with ethical standards

This article is not a direct report of any investigation with the involvement of human or animal subjects performed by any of the authors.

Funding

No funding was received for this study.

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

This article has no direct invlovement of human participants or animals for evaluation by any of the authors.

Informed consent

Statement of informed consent was not applicable since the manuscript is not a direct report of any investigation with the involvement of human subjects.

References

  1. 1.
    Jaffray DA (2012) Image-guided radiotherapy: from current concept to future perspectives. Nat Rev Clin Oncol 9(12):688–699Google Scholar
  2. 2.
    Orth M, Lauber K, Niyazi M, Friedl AA, Li M, Maihöfer C, Schüttrumpf L, Ernst A, Niemöller OM, Belka C (2014) Current concepts in clinical radiation oncology. Radiat Environ Biophys 53(1):1–29Google Scholar
  3. 3.
    Barton MB, Jacob S, Shafiq J, Wong K, Thompson SR, Hanna TP, Delaney GP (2014) Estimating the demand for radiotherapy from the evidence: a review of changes from 2003 to 2012. Radiother Oncol 112(1):140–144Google Scholar
  4. 4.
    Salama AK, Postow MA, Salama JK (2016) Irradiation and immunotherapy: from concept to the clinic. Cancer 122(11):1659–1671Google Scholar
  5. 5.
    Mole RH (1953) Whole body irradiation; radiobiology or medicine? Br J Radiol 26(305):234–241Google Scholar
  6. 6.
    Kaminski JM, Shinohara E, Summers JB, Niermann KJ, Morimoto A, Brousal J (2005) The controversial abscopal effect. Cancer Treat Rev 31(3):159–172Google Scholar
  7. 7.
    Jatoi I, Benson JR, Kunkler I (2018) Hypothesis: can the abscopal effect explain the impact of adjuvant radiotherapy on breast cancer mortality? NPJ Breast Cancer 4:8Google Scholar
  8. 8.
    Rontgen WC (1896) On a new kind of rays. Science 3:227–231Google Scholar
  9. 9.
    Becquerel AH (1896) Sur les radiations ´emises par phosphorescence. Rend Acad Sci 122:420–421Google Scholar
  10. 10.
    Curie P, Curie M (1898) Sur une substance nouvelle radioactive, contenue dans la pechblende. C R Acad Sci 127:125Google Scholar
  11. 11.
    Schäfer W, Witte E (1932) Über eine neue Körperhöhlenröntgenröhre zur Bestrahulung von Uterustumoren. Strahlentherapie 44:283Google Scholar
  12. 12.
    Becquerel AH, Curie P (1901) Action physiologique des rayons de radium. C R Acad Sci 132:1289–1291Google Scholar
  13. 13.
    Coolidge WD (1913) A powerful Rontgen ray tube with a pure electron discharge. Phys Rev 2:409–413Google Scholar
  14. 14.
    Grubbe EH (1933) Priority in the therapeutic use of X-rays. Radiology. 21:156–162Google Scholar
  15. 15.
    Thoraeus RA (1932) A study of ionization method for measuring the intensity and absorption of roentgen rays and of the efficiency of different filters used in therapy. Acta Radiol 18:1–86Google Scholar
  16. 16.
    Thariat J, Hannoun-Levi JM, Sun Myint A, Vuong T, Gerard JP (2013) Past, present, and future of radiotherapy for the benefit of patients. Nat Rev Clin Oncol 10(1):52–60Google Scholar
  17. 17.
    Slater JM (2012) From X-rays to ion beams: a short history of radiation therapy. In: Linz U (ed) Ion beam therapy, biological and medical physics, biomedical engineering. Springer-Verlag, Berlin, pp 3–16Google Scholar
  18. 18.
    Gianfaldoni S, Gianfaldoni R, Wollina U, Lotti J, Tchernev G, Lotti T (2017) An overview on radiotherapy: from its history to its current applications in dermatology. Open Access Maced J Med Sci 5(4):521–525Google Scholar
  19. 19.
    Ross GM (1999) Induction of cell death by radiotherapy. Endocr Relat Cancer 6(1):41–44Google Scholar
  20. 20.
    Vatner RE, Cooper BT, Vanpouille-Box C, Demaria S, Formenti SC (2014) Combinations of immunotherapy and radiation in cancer therapy. Front Oncol 4:325Google Scholar
  21. 21.
    Kamrava M, Bernstein MB, Camphausen K, Hodge JW (2009) Combining radiation, immunotherapy, and antiangiogenesis agents in the management of cancer: the Three Musketeers or just another quixotic combination? Mol BioSyst 5(11):1262–1270Google Scholar
  22. 22.
    Twyman-Saint Victor C, Rech AJ, Maity A, Rengan R, Pauken KE, Stelekati E, Benci JL, Xu B, Dada H, Odorizzi PM, Herati RS, Mansfield KD, Patsch D, Amaravadi RK, Schuchter LM, Ishwaran H, Mick R, Pryma DA, Xu X, Feldman MD, Gangadhar TC, Hahn SM, Wherry EJ, Vonderheide RH, Minn AJ (2015) Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature. 520(7547):373–377Google Scholar
  23. 23.
    Hodge JW, Guha C, Neefjes J, Gulley JL (2008) Synergizing radiation therapy and immunotherapy for curing incurable cancers. Opportunities and challenges. Oncology (Williston Park) 22(9):1064–1070 discussion 1075, 1080-1061, 1084Google Scholar
  24. 24.
    Bitran J (2019) The abscopal effect exists in non-small cell lung cancer: a case report and review of the literature. Cureus. 11(2):e4118Google Scholar
  25. 25.
    Kim JO, Kim CA (2019) Abscopal resolution of a hepatic metastasis in a patient with metastatic cholangiocarcinoma following radical stereotactic body radiotherapy to a synchronous early stage non-small cell lung cancer. Cureus. 11(2):e4082Google Scholar
  26. 26.
    Lin X, Lu T, Xie Z, Qin Y, Liu M, Xie X, Li S, Zhou C (2019) Extracranial abscopal effect induced by combining immunotherapy with brain radiotherapy in a patient with lung adenocarcinoma: a case report and literature review. Thorac Cancer 10(5):1272–1275Google Scholar
  27. 27.
    Hamilton AJ, Seid J, Verdecchia K, Chuba P (2018) Abscopal effect after radiosurgery for solitary brain metastasis from non-small cell lung cancer. Cureus. 10(12):e3777Google Scholar
  28. 28.
    Britschgi C, Riesterer O, Burger IA, Guckenberger M, Curioni-Fontecedro A (2018) Report of an abscopal effect induced by stereotactic body radiotherapy and nivolumab in a patient with metastatic non-small cell lung cancer. Radiat Oncol 13(1):102Google Scholar
  29. 29.
    Cong Y, Shen G, Wu S, Hao R (2017) Abscopal regression following SABR for non-small-cell-lung cancer: a case report. Cancer Biol Ther. 18(1):1–3Google Scholar
  30. 30.
    Katayama K, Tamiya A, Koba T, Fukuda S, Atagi S (2017) An abscopal response to radiation therapy in a patient with metastatic non-small cell lung cancer: a case report. J Cancer Sci Ther 9:365–367Google Scholar
  31. 31.
    Cummings AL, Kaprealian TB, Sarantopoulos AP, Mendenhall MA, Goldman JW An abscopal effect in a case of neuroendocrine atypical carcinoid lung cancer. Appl Radiation Oncol 2017:39–39Google Scholar
  32. 32.
    Komatsu T, Nakamura K, Kawase A (2017) Abscopal effect of nivolumab in a patient with primary lung cancer. J Thorac Oncol 12(9):e143–e144Google Scholar
  33. 33.
    Golden EB, Demaria S, Schiff PB, Chachoua A, Formenti SC (2013) An abscopal response to radiation and ipilimumab in a patient with metastatic non-small cell lung cancer. Cancer Immunol Res 1(6):365–372Google Scholar
  34. 34.
    Siva S, Callahan J, MacManus MP, Martin O, Hicks RJ, Ball DL (2013) Abscopal [corrected] effects after conventional and stereotactic lung irradiation of non-small-cell lung cancer. J Thorac Oncol 8(8):e71–e72Google Scholar
  35. 35.
    Yoon SM, Lee JS (2012) Case of abscopal effect with metastatic non-small-cell lung cancer. Oncothermia J 5:53–57Google Scholar
  36. 36.
    Tsui JM, Mihalcioiu C, Cury FL (2018) Abscopal effect in a stage IV melanoma patient who progressed on pembrolizumab. Cureus. 10(2):e2238Google Scholar
  37. 37.
    Sims-Mourtada J, Sims-Mourtada S, Casteneda S et al (2018) Dosimetric characterization of an abscopal response in a patient with oligometastatic melanoma undergoing concurrent treatment with pembrolizumab and stereotactic body radiotherapy. Cancer Stud Mol Med 4:1–4Google Scholar
  38. 38.
    Komori T, Otsuka A, Irie H, Horiguchi A, Honda T, Kabashima K (2018) Drastic effect on giant lung metastatic melanoma by sequential administration of nivolumab with ipilimumab/radiation combination therapy. J Dermatol 45(1):e7–e8Google Scholar
  39. 39.
    Sperduto W, King DM, Watanabe Y, Lou E, Sperduto PW (2017) Case report of extended survival and quality of life in a melanoma patient with multiple brain metastases and review of literature. Cureus. 9(12):e1947Google Scholar
  40. 40.
    Fujimura T, Kambayashi Y, Furudate S, Hidaka T, Sato Y, Tanita K, Tono H, Tsukada A, Hashimoto A, Aiba S (2017) Successful treatment of multiple in-transit melanomas on the leg with intensity-modulated radiotherapy and immune checkpoint inhibitors: report of two cases. J Dermatol 44(5):592–595Google Scholar
  41. 41.
    Okwan-Duodu D, Pollack BP, Lawson D, Khan MK (2015) Role of radiation therapy as immune activator in the era of modern immunotherapy for metastatic malignant melanoma. Am J Clin Oncol 38(1):119–125Google Scholar
  42. 42.
    Teulings HE, Tjin EP, Willemsen KJ et al (2013) Radiation-induced melanoma-associated leucoderma, systemic antimelanoma immunity and disease-free survival in a patient with advanced-stage melanoma: a case report and immunological analysis. Br J Dermatol 168(4):733–738Google Scholar
  43. 43.
    Stamell EF, Wolchok JD, Gnjatic S, Lee NY, Brownell I (2013) The abscopal effect associated with a systemic anti-melanoma immune response. Int J Radiat Oncol Biol Phys 85(2):293–295Google Scholar
  44. 44.
    Postow MA, Callahan MK, Barker CA, Yamada Y, Yuan J, Kitano S, Mu Z, Rasalan T, Adamow M, Ritter E, Sedrak C, Jungbluth AA, Chua R, Yang AS, Roman RA, Rosner S, Benson B, Allison JP, Lesokhin AM, Gnjatic S, Wolchok JD (2012) Immunologic correlates of the abscopal effect in a patient with melanoma. N Engl J Med 366(10):925–931Google Scholar
  45. 45.
    Hiniker SM, Chen DS, Reddy S, Chang DT, Jones JC, Mollick JA, Swetter SM, Knox SJ (2012) A systemic complete response of metastatic melanoma to local radiation and immunotherapy. Transl Oncol 5(6):404–407Google Scholar
  46. 46.
    Kingsley DP (1975) An interesting case of possible abscopal effect in malignant melanoma. Br J Radiol 48(574):863–866Google Scholar
  47. 47.
    Orton A, Wright J, Buchmann L, Randall L, Hitchcock YJ (2016) A case of complete abscopal response in high-grade pleiomorphic sarcoma treated with radiotherapy alone. Cureus. 8(10):e821Google Scholar
  48. 48.
    Cotter SE, Dunn GP, Collins KM, Sahni D, Zukotynski KA, Hansen JL, O’Farrell DA, Ng AK, Devlin PM, Wang LC (2011) Abscopal effect in a patient with metastatic Merkel cell carcinoma following radiation therapy: potential role of induced antitumor immunity. Arch Dermatol 147(7):870–872Google Scholar
  49. 49.
    Giulio F, Donato P, Beatrice D et al (2018) A case report series of renal cell carcinoma patients treated with Nivolumab and radiotherapy. J Oncol Res Ther.  https://doi.org/10.29011/22574-29710X.000050
  50. 50.
    LaPlant Q, Deselm C, Lockney NA, Hsieh J, Yamada Y (2017) Potential abscopal response to dual checkpoint blockade in RCC after reirradiation using dose-painting SBRT. Pract Radiat Oncol 7(6):396–399Google Scholar
  51. 51.
    Ishiyama H, Teh BS, Ren H, Chiang S, Tann A, Blanco AI, Paulino AC, Amato R (2012) Spontaneous regression of thoracic metastases while progression of brain metastases after stereotactic radiosurgery and stereotactic body radiotherapy for metastatic renal cell carcinoma: abscopal effect prevented by the blood-brain barrier? Clin Genitourin Cancer 10(3):196–198Google Scholar
  52. 52.
    Wersall PJ, Blomgren H, Pisa P, Lax I, Kalkner KM, Svedman C (2006) Regression of non-irradiated metastases after extracranial stereotactic radiotherapy in metastatic renal cell carcinoma. Acta Oncol 45(4):493–497Google Scholar
  53. 53.
    MacManus MP, Harte RJ, Stranex S (1994) Spontaneous regression of metastatic renal cell carcinoma following palliative irradiation of the primary tumour. Ir J Med Sci 163(10):461–463Google Scholar
  54. 54.
    Fairlamb DJ (1981) Spontaneous regression of metastases of renal cancer: a report of two cases including the first recorded regression following irradiation of a dominant metastasis and review of the world literature. Cancer. 47(8):2102–2106Google Scholar
  55. 55.
    Lock M, Muinuddin A, Kocha WI, Dinniwell R, Rodrigues G, D’Souza D (2015) Abscopal effects: case report and emerging opportunities. Cureus. 7(10):e344Google Scholar
  56. 56.
    Okuma K, Yamashita H, Niibe Y, Hayakawa K, Nakagawa K (2011) Abscopal effect of radiation on lung metastases of hepatocellular carcinoma: a case report. J Med Case Rep 5:111Google Scholar
  57. 57.
    Nakanishi M, Chuma M, Hige S, Asaka M (2008) Abscopal effect on hepatocellular carcinoma. Am J Gastroenterol 103(5):1320–1321Google Scholar
  58. 58.
    Nam SW, Han JY, Kim JI et al (2005) Spontaneous regression of a large hepatocellular carcinoma with skull metastasis. J Gastroenterol Hepatol 20(3):488–492Google Scholar
  59. 59.
    Ohba K, Omagari K, Nakamura T, Ikuno N, Saeki S, Matsuo I, Kinoshita H, Masuda J, Hazama H, Sakamoto I, Kohno S (1998) Abscopal regression of hepatocellular carcinoma after radiotherapy for bone metastasis. Gut. 43(4):575–577Google Scholar
  60. 60.
    Ebner DK, Kamada T, Yamada S (2017) Abscopal effect in recurrent colorectal cancer treated with carbon-ion radiation therapy: 2 case reports. Adv Radiat Oncol 2(3):333–338Google Scholar
  61. 61.
    Joe MB, Lum JJ, Watson PH, Tonseth RP, McGhie JP, Truong PT (2017) Radiation generates an abscopal response and complete resolution of metastatic squamous cell carcinoma of the anal canal: a case report. J Gastrointest Oncol 8(6):E84–E89Google Scholar
  62. 62.
    Smith JA Jr, Herr HW (1980) Spontaneous regression of pulmonary metastases from transitional cell carcinoma. Cancer. 46(6):1499–1502Google Scholar
  63. 63.
    Lome LG, Navani S, Aral IM (1970) Spontaneous regression of pulmonary metastases from transitional cell carcinoma of the bladder. Cancer. 26(2):415–418Google Scholar
  64. 64.
    Takaya M, Niibe Y, Tsunoda S, Jobo T, Imai M, Kotani S, Unno N, Hayakawa K (2007) Abscopal effect of radiation on toruliform para-aortic lymph node metastases of advanced uterine cervical carcinoma--a case report. Anticancer Res 27(1B):499–503Google Scholar
  65. 65.
    Rees GJ, Ross CM (1983) Abscopal regression following radiotherapy for adenocarcinoma. Br J Radiol 56(661):63–66Google Scholar
  66. 66.
    Leung HW, Wang SY, Jin-Jhih H, Chan AL (2018) Abscopal effect of radiation on bone metastases of breast cancer: a case report. Cancer Biol Ther. 19(1):20–24Google Scholar
  67. 67.
    Azami A, Suzuki N, Azami Y, Seto I, Sato A, Takano Y, Abe T, Teranishi Y, Tachibana K, Ohtake T (2018) Abscopal effect following radiation monotherapy in breast cancer: a case report. Mol Clin Oncol 9(3):283–286Google Scholar
  68. 68.
    Tubin S, Casamassima F, Menichelli C, Pastore G, Fanelli M, Crisci R (2012) A case report on metastatic thyroid carcinoma: radiation-induced bystander or abscopal effect? J Cancer Sci Ther. 4:408–411Google Scholar
  69. 69.
    Sato H, Suzuki Y, Yoshimoto Y, Noda SE, Murata K, Takakusagi Y, Okazaki A, Sekihara T, Nakano T (2017) An abscopal effect in a case of concomitant treatment of locally and peritoneally recurrent gastric cancer using adoptive T-cell immunotherapy and radiotherapy. Clin Case Rep 5(4):380–384Google Scholar
  70. 70.
    Shi F, Wang X, Teng F, Kong L, Yu J (2017) Abscopal effect of metastatic pancreatic cancer after local radiotherapy and granulocyte-macrophage colony-stimulating factor therapy. Cancer Biol Ther 18(3):137–141Google Scholar
  71. 71.
    Lesueur P, Chevalier F, Stefan D, Habrand JL, Lerouge D, Gervais R (2017) Review of the mechanisms involved in the abscopal effect and future directions with a focus on thymic carcinoma. Tumori. 103(3):217–222Google Scholar
  72. 72.
    Schaub S, Stewart R, Sandison G et al (2018) Does neutron radiation therapy potentiate an immune response to Merkel cell carcinoma? Int J Particle Ther 5:183–195Google Scholar
  73. 73.
    Barsky AR, Cengel KA, Katz SI, Sterman DH, Simone CB (2019) First-ever abscopal effect after palliative radiotherapy and Immuno-gene therapy for malignant pleural mesothelioma. Cureus. 11(2):e4102Google Scholar
  74. 74.
    Desar IM, Braam PM, Kaal SE, Gerritsen WR, Oyen WJ, van der Graaf WT (2016) Abscopal effect of radiotherapy in a patient with metastatic diffuse-type giant cell tumor. Acta Oncol 55(12):1510–1512Google Scholar
  75. 75.
    Ehlers G, Fridman M (1973) Abscopal effect of radiation in papillary adenocarcinoma. Br J Radiol 46(543):220–222Google Scholar
  76. 76.
    Golden EB, Chhabra A, Chachoua A, Adams S, Donach M, Fenton-Kerimian M, Friedman K, Ponzo F, Babb JS, Goldberg J, Demaria S, Formenti SC (2015) Local radiotherapy and granulocyte-macrophage colony-stimulating factor to generate abscopal responses in patients with metastatic solid tumours: a proof-of-principle trial. Lancet Oncol 16(7):795–803Google Scholar
  77. 77.
    Hiniker SM, Reddy SA, Maecker HT, Subrahmanyam PB, Rosenberg-Hasson Y, Swetter SM, Saha S, Shura L, Knox SJ (2016) A prospective clinical trial combining radiation therapy with systemic immunotherapy in metastatic melanoma. Int J Radiat Oncol Biol Phys 96(3):578–588Google Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.University Cancer and Diagnostic CentersHoustonUSA

Personalised recommendations