Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Safety of combining radiotherapy with immune-checkpoint inhibition

Abstract

Immune-checkpoint inhibitors targeting cytotoxic T- lymphocyte antigen 4 (CTLA-4), programmed cell death protein 1 (PD-1), or programmed cell death 1 ligand 1 (PD-L1) have transformed the care of patients with a wide range of advanced-stage malignancies. More than half of these patients will also have an indication for treatment with radiotherapy. The effects of both radiotherapy and immune-checkpoint inhibition (ICI) involve a complex interplay with the innate and adaptive immune systems, and accumulating evidence suggests that, under certain circumstances, the effects of radiotherapy synergize with those of ICI to augment the antitumour responses typically observed with either modality alone and thus improve clinical outcomes. However, the mechanisms by which radiotherapy and immune-checkpoint inhibitors synergistically modulate the immune response might also affect both the type and severity of treatment-related toxicities. Moreover, in patients receiving immune-checkpoint inhibitors, the development of immune-related adverse events has been linked with superior treatment responses and patient survival durations, suggesting a relationship between the antitumour and adverse autoimmune effects of these agents. In this Review, we discuss the emerging data on toxicity profiles related to immune-checkpoint inhibitors and radiotherapy, both separately and in combination, their potential mechanisms, and the approaches to managing these toxicities.

Key points

  • The effects of radiotherapy on both tumours and nonmalignant tissues involve a complex interplay with the immune system, potentially resulting in both immunostimulatory and immunosuppressive effects.

  • Under certain circumstances, radiotherapy might augment the antitumour effects of immune-checkpoint inhibition (ICI) by releasing endogenous danger signals and cytokines, increasing the presentation of tumour-associated antigens on antigen-presenting cells, and stimulating diversification of the T cell repertoire.

  • Combination therapy with radiotherapy and ICI might affect both the type and severity of treatment-related toxicities, especially immune-related adverse events.

  • Data from numerous retrospective series and a handful of prospective studies, both single-arm and randomized, provide burgeoning evidence that the combination of palliative radiotherapy and ICI is safe overall without a substantial site-specific increase in adverse events.

  • The available evidence suggests that ICI following definitive chemoradiotherapy for non-small-cell lung cancer does not increase the incidence of grade ≥3 pneumonitis over either treatment modality alone.

  • Addition of ICI to high-dose stereotactic intracranial radiotherapy for brain metastases might increase the risk of treatment-related brain necrosis.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Clinical examples of common toxicities seen with radiotherapy and immune-checkpoint inhibition.
Fig. 2: Variations in radiation exposure with different radiotherapy techniques.
Fig. 3: Synergistic effects of radiotherapy and immune-checkpoint inhibition.

Similar content being viewed by others

References

  1. Lederman, M. The early history of radiotherapy: 1895–1939. Int. J. Radiat. Oncol. 7, 639–648 (1981).

    CAS  Google Scholar 

  2. Barton, M. B. et al. Estimating the demand for radiotherapy from the evidence: a review of changes from 2003 to 2012. Radiother. Oncol. 112, 140–144 (2014).

    PubMed  Google Scholar 

  3. Delaney, G., Jacob, S., Featherstone, C. & Barton, M. The role of radiotherapy in cancer treatment. Cancer 104, 1129–1137 (2005).

    PubMed  Google Scholar 

  4. Citrin, D. E. Recent developments in radiotherapy. N. Engl. J. Med. 377, 1065–1075 (2017).

    CAS  PubMed  Google Scholar 

  5. Amaravadi, R. K. & Thompson, C. B. The roles of therapy-induced autophagy and necrosis in cancer treatment. Clin. Cancer Res. 13, 7271–7279 (2007).

    CAS  PubMed  Google Scholar 

  6. Rouschop, K. M. A. et al. Autophagy is required during cycling hypoxia to lower production of reactive oxygen species. Radiother. Oncol. 92, 411–416 (2009).

    CAS  PubMed  Google Scholar 

  7. Twyman-Saint Victor, C. et al. Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature 520, 373–377 (2015).

    CAS  PubMed  Google Scholar 

  8. Ludgate, C. M. Optimizing cancer treatments to induce an acute immune response: radiation abscopal effects, PAMPs, and DAMPs. Clin. Cancer Res. 18, 4522–4525 (2012).

    CAS  PubMed  Google Scholar 

  9. Sridharan, V. et al. Effects of definitive chemoradiation on circulating immunologic angiogenic cytokines in head and neck cancer patients. J. Immunother. Cancer 4, 32 (2016).

    PubMed  PubMed Central  Google Scholar 

  10. de Gonzalez, A. B. et al. Proportion of second cancers attributable to radiotherapy treatment in adults: a cohort study in the US SEER cancer registries. Lancet Oncol. 12, 353–360 (2011).

    PubMed Central  Google Scholar 

  11. Schaapveld, M. et al. Second cancer risk up to 40 years after treatment for Hodgkin’s Lymphoma. N. Engl. J. Med. 373, 2499–2511 (2015).

    CAS  PubMed  Google Scholar 

  12. Journy, N. M. Y., Morton, L. M., Kleinerman, R. A., Bekelman, J. E. & Berrington de Gonzalez, A. Second primary cancers after intensity-modulated versus 3-dimensional conformal radiation therapy for prostate cancer. JAMA Oncol. 2, 1368 (2016).

    PubMed  Google Scholar 

  13. Bhakta, N. et al. The cumulative burden of surviving childhood cancer: an initial report from the St Jude Lifetime Cohort Study (SJLIFE). Lancet 390, 2569–2582 (2017).

    PubMed  PubMed Central  Google Scholar 

  14. Turcotte, L. M. et al. Temporal trends in treatment and subsequent neoplasm risk among 5-year survivors of childhood cancer, 1970–2015. JAMA 317, 814 (2017).

    PubMed  PubMed Central  Google Scholar 

  15. Larkin, J. et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N. Engl. J. Med. 373, 23–34 (2015).

    PubMed  PubMed Central  Google Scholar 

  16. Borghaei, H. et al. Nivolumab versus docetaxel in advanced nonsquamous non–small-cell lung cancer. N. Engl. J. Med. 373, 1627–1639 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Robert, C. et al. Nivolumab in previously untreated melanoma without BRAF mutation. N. Engl. J. Med. 372, 320–330 (2015).

    CAS  PubMed  Google Scholar 

  18. Robert, C. et al. Pembrolizumab versus ipilimumab in advanced melanoma. N. Engl. J. Med. 372, 2521–2532 (2015).

    CAS  PubMed  Google Scholar 

  19. Topalian, S. L. et al. Safety, activity, and immune correlates of anti–PD-1 antibody in cancer. N. Engl. J. Med. 366, 2443–2454 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Ansell, S. M. et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. N. Engl. J. Med. 372, 311–319 (2015).

    PubMed  Google Scholar 

  21. Peggs, K. S., Quezada, S. A., Chambers, C. A., Korman, A. J. & Allison, J. P. Blockade of CTLA-4 on both effector and regulatory T cell compartments contributes to the antitumor activity of anti–CTLA-4 antibodies. J. Exp. Med. 206, 1717–1725 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Azuma, M. et al. B70 antigen is a second ligand for CTLA-4 and CD28. Nature 366, 76–79 (1993).

    CAS  PubMed  Google Scholar 

  23. Freeman, G. J. et al. Cloning of B7-2: a CTLA-4 counter-receptor that costimulates human T cell proliferation. Science 262, 909–911 (1993).

    CAS  PubMed  Google Scholar 

  24. Waterhouse, P. et al. Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4. Science 270, 985–988 (1995).

    CAS  PubMed  Google Scholar 

  25. Khattri, R., Auger, J. A., Griffin, M. D., Sharpe, A. H. & Bluestone, J. A. Lymphoproliferative disorder in CTLA-4 knockout mice is characterized by CD28-regulated activation of Th2 responses. J. Immunol. 162, 5784–5791 (1999).

    CAS  PubMed  Google Scholar 

  26. Smigiel, K. S., Srivastava, S., Stolley, J. M. & Campbell, D. J. Regulatory T cell homeostasis: steady-state maintenance and modulation during inflammation. Immunol. Rev. 259, 40–59 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Ueda, H. et al. Association of the T cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature 423, 506–511 (2003).

    CAS  PubMed  Google Scholar 

  28. Vaidya, B. et al. An association between the CTLA4 exon 1 polymorphism and early rheumatoid arthritis with autoimmune endocrinopathies. Rheumatology 41, 180–183 (2002).

    CAS  PubMed  Google Scholar 

  29. Zhernakova, A. et al. CTLA4 is differentially associated with autoimmune diseases in the Dutch population. Hum. Genet. 118, 58–66 (2005).

    CAS  PubMed  Google Scholar 

  30. Fernández-Mestre, M. et al. Influence of CTLA-4 gene polymorphism in autoimmune and infectious diseases. Hum. Immunol. 70, 532–535 (2009).

    PubMed  Google Scholar 

  31. Hudson, L., Rocca, K., Song, Y. & Pandey, J. CTLA-4 gene polymorphisms in systemic lupus erythematosus: a highly significant association with a determinant in the promoter region. Hum. Genet. 111, 452–455 (2002).

    CAS  PubMed  Google Scholar 

  32. Blomhoff, A. et al. Polymorphisms in the cytotoxic T lymphocyte antigen-4 gene region confer susceptibility to Addison’s disease. J. Clin. Endocrinol. Metab. 89, 3474–3476 (2004).

    CAS  PubMed  Google Scholar 

  33. Francisco, L. M., Sage, P. T. & Sharpe, A. H. The PD-1 pathway in tolerance and autoimmunity. Immunol. Rev. 236, 219–242 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Okazaki, T., Chikuma, S., Iwai, Y., Fagarasan, S. & Honjo, T. A rheostat for immune responses: the unique properties of PD-1 and their advantages for clinical application. Nat. Immunol. 14, 1212–1218 (2013).

    CAS  PubMed  Google Scholar 

  35. Shi, F. et al. PD-1 and PD-L1 upregulation promotes CD8+ T cell apoptosis and postoperative recurrence in hepatocellular carcinoma patients. Int. J. Cancer 128, 887–896 (2011).

    CAS  PubMed  Google Scholar 

  36. Kataoka, K. et al. Aberrant PD-L1 expression through 3′-UTR disruption in multiple cancers. Nature 534, 402–406 (2016).

    CAS  PubMed  Google Scholar 

  37. Nishimura, H. et al. Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice. Science 291, 319–322 (2001).

    CAS  PubMed  Google Scholar 

  38. Nishimura, H., Nose, M., Hiai, H., Minato, N. & Honjo, T. Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity 11, 141–151 (1999).

    CAS  PubMed  Google Scholar 

  39. Boutros, C. et al. Safety profiles of anti-CTLA-4 and anti-PD-1 antibodies alone and in combination. Nat. Rev. Clin. Oncol. 13, 473–486 (2016).

    CAS  PubMed  Google Scholar 

  40. Postow, M. A. et al. Immunologic correlates of the abscopal effect in a patient with melanoma. N. Engl. J. Med. 366, 925–931 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Mole, R. H. Whole body irradiation; radiobiology or medicine? Br. J. Radiol 26, 234–241 (1953).

    CAS  PubMed  Google Scholar 

  42. Demaria, S. et al. Ionizing radiation inhibition of distant untreated tumors (abscopal effect) is immune mediated. Int. J. Radiat. Oncol. 58, 862–870 (2004).

    Google Scholar 

  43. Weichselbaum, R. R., Liang, H., Deng, L. & Fu, Y. X. Radiotherapy and immunotherapy: a beneficial liaison? Nat. Rev. Clin. Oncol. 14, 365–379 (2017).

    CAS  PubMed  Google Scholar 

  44. Cappelli, L. C., Shah, A. A. & Bingham, C. O. Immune-related adverse effects of cancer immunotherapy — implications for rheumatology. Rheum. Dis. Clin. North Am. 43, 65–78 (2017).

    PubMed  Google Scholar 

  45. Stone, H., Peters, L. & Milas, L. Effect of host immune capability on radiocurability and subsequent transplantability of a murine fibrosarcoma. J. Natl Cancer Inst. 63, 1229–1235 (1979).

    CAS  PubMed  Google Scholar 

  46. Ngwa, W. et al. Using immunotherapy to boost the abscopal effect. Nat. Rev. Cancer 18, 313–322 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Deng, L. et al. Irradiation and anti–PD-L1 treatment synergistically promote antitumor immunity in mice. J. Clin. Invest. 124, 687–695 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Schaue, D., Kachikwu, E. L. & McBride, W. H. Cytokines in radiobiological responses: a review. Radiat. Res. 178, 505–523 (2012).

    PubMed  PubMed Central  Google Scholar 

  49. Demaria, S. & Formenti, S. C. Radiation as an immunological adjuvant: current evidence on dose and fractionation. Front. Oncol. 2, 153 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Demaria, S. & Formenti, S. C. Role of T lymphocytes in tumor response to radiotherapy. Front. Oncol. 2, 95 (2012).

    PubMed  PubMed Central  Google Scholar 

  51. Lugade, A. A. et al. Local radiation therapy of B16 melanoma tumors increases the generation of tumor antigen-specific effector cells that traffic to the tumor. J. Immunol. 174, 7516–7523 (2005).

    CAS  PubMed  Google Scholar 

  52. Sharabi, A. B. et al. Stereotactic radiation therapy augments antigen-specific PD-1-mediated antitumor immune responses via cross-presentation of tumor antigen. Cancer Immunol. Res. 3, 345–355 (2015).

    CAS  PubMed  Google Scholar 

  53. Gupta, A. et al. Radiotherapy promotes tumor-specific effector CD8+ T cells via dendritic cell activation. J. Immunol. 189, 558–566 (2012).

    CAS  PubMed  Google Scholar 

  54. Abuodeh, Y., Venkat, P. & Kim, S. Systematic review of case reports on the abscopal effect. Curr. Probl. Cancer 40, 25–37 (2016).

    PubMed  Google Scholar 

  55. Formenti, S. C. & Demaria, S. Combining radiotherapy and cancer immunotherapy: a paradigm shift. J. Natl Cancer Inst. 105, 256–265 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Kalbasi, A., June, C. H., Haas, N. & Vapiwala, N. Radiation and immunotherapy: a synergistic combination. J. Clin. Invest. 123, 2756–2763 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Sharabi, A. B., Lim, M., DeWeese, T. L. & Drake, C. G. Radiation and checkpoint blockade immunotherapy: radiosensitisation and potential mechanisms of synergy. Lancet Oncol. 16, e498–e509 (2015).

    PubMed  Google Scholar 

  58. Kachikwu, E. L. et al. Radiation enhances regulatory T cell representation. Int. J. Radiat. Oncol. Biol. Phys. 81, 1128–1135 (2011).

    PubMed  Google Scholar 

  59. Persa, E., Balogh, A., Sáfrány, G. & Lumniczky, K. The effect of ionizing radiation on regulatory T cells in health and disease. Cancer Lett. 368, 252–261 (2015).

    CAS  PubMed  Google Scholar 

  60. Facciabene, A., Motz, G. T. & Coukos, G. T-regulatory cells: key players in tumor immune escape and angiogenesis. Cancer Res. 72, 2162–2171 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Balogh, A. et al. The effect of ionizing radiation on the homeostasis and functional integrity of murine splenic regulatory T cells. Inflamm Res. 62, 201–212 (2013).

    CAS  PubMed  Google Scholar 

  62. Dewan, M. Z. et al. Fractionated but not single-dose radiotherapy induces an immune-mediated abscopal effect when combined with anti-CTLA-4 antibody. Clin. Cancer Res. 15, 5379–5388 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Bernstein, M. B., Krishnan, S., Hodge, J. W. & Chang, J. Y. Immunotherapy and stereotactic ablative radiotherapy (ISABR): a curative approach? Nat. Rev. Clin. Oncol. 13, 516–524 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Vanpouille-Box, C. et al. DNA exonuclease Trex1 regulates radiotherapy-induced tumour immunogenicity. Nat. Commun. 8, 15618 (2017).

    PubMed  PubMed Central  Google Scholar 

  65. DuPage, M. & Jacks, T. Genetically engineered mouse models of cancer reveal new insights about the antitumor immune response. Curr. Opin. Immunol. 25, 192–199 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Dranoff, G. Experimental mouse tumour models: what can be learnt about human cancer immunology? Nat. Rev. Immunol. 12, 61–66 (2011).

    PubMed  Google Scholar 

  67. Ryder, M., Callahan, M., Postow, M. A., Wolchok, J. & Fagin, J. A. Endocrine-related adverse events following ipilimumab in patients with advanced melanoma: a comprehensive retrospective review from a single institution. Endocr. Relat. Cancer 21, 371–381 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Michot, J. M. et al. Immune-related adverse events with immune checkpoint blockade: a comprehensive review. Eur. J. Cancer 54, 139–148 (2016).

    CAS  PubMed  Google Scholar 

  69. Weber, J. S. et al. Phase I/II study of ipilimumab for patients with metastatic melanoma. J. Clin. Oncol. 26, 5950–5956 (2008).

    CAS  PubMed  Google Scholar 

  70. Di Giacomo, A. M. et al. Ipilimumab and fotemustine in patients with advanced melanoma (NIBIT-M1): an open-label, single-arm phase 2 trial. Lancet Oncol. 13, 879–8868 (2012).

    PubMed  Google Scholar 

  71. Margolin, K. et al. Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial. Lancet Oncol. 13, 459–465 (2012).

    CAS  PubMed  Google Scholar 

  72. Wolchok, J. D. et al. Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study. Lancet Oncol. 11, 155–164 (2010).

    CAS  PubMed  Google Scholar 

  73. Robert, C. et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N. Engl. J. Med. 364, 2517–2526 (2011).

    CAS  PubMed  Google Scholar 

  74. Brahmer, J. R. et al. Phase I study of single-agent anti–programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J. Clin. Oncol. 28, 3167–3175 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Topalian, S. L. et al. Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. J. Clin. Oncol. 32, 1020–1030 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Robert, C. et al. Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet 384, 1109–1117 (2014).

    CAS  PubMed  Google Scholar 

  77. Ribas, A. et al. Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol. 16, 908–918 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Barroso-Sousa, R. et al. Incidence of endocrine dysfunction following the use of different immune checkpoint inhibitor regimens: a systematic review and meta-analysis. JAMA Oncol. 4, 173–182 (2018).

    PubMed  Google Scholar 

  79. Hassel, J. C. et al. Combined immune checkpoint blockade (anti-PD-1/anti-CTLA-4): evaluation and management of adverse drug reactions. Cancer Treat. Rev. 57, 36–49 (2017).

    CAS  PubMed  Google Scholar 

  80. Brahmer, J. R. et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology Clinical Practice Guideline. J. Clin. Oncol. 36, 1–55 (2018).

    Google Scholar 

  81. Dick, J. et al. Use of LDH and autoimmune side effects to predict response to ipilimumab treatment. Immunotherapy 8, 1033–1044 (2016).

    CAS  PubMed  Google Scholar 

  82. Feng, S. et al. Pembrolizumab-induced encephalopathy: a review of neurological toxicities with immune checkpoint inhibitors. J. Thorac Oncol. 12, 1626–1635 (2017).

    PubMed  Google Scholar 

  83. Hwang, W. L. et al. Clinical outcomes in patients with metastatic lung cancer treated with PD-1/PD-L1 inhibitors and thoracic radiotherapy. JAMA Oncol. 4, 253–255 (2018).

    PubMed  Google Scholar 

  84. Haratani, K. et al. Association of immune-related adverse events with nivolumab efficacy in non–small-cell lung cancer. JAMA Oncol. 4, 374–378 (2018).

    PubMed  Google Scholar 

  85. Weber, J. S. et al. Safety profile of nivolumab monotherapy: a pooled analysis of patients with advanced melanoma. J. Clin. Oncol. 35, 785–792 (2017).

    CAS  PubMed  Google Scholar 

  86. Snyder, A. et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N. Engl. J. Med. 371, 2189–2199 (2014).

    PubMed  PubMed Central  Google Scholar 

  87. Vétizou, M. et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science 350, 1079–1084 (2015).

    PubMed  PubMed Central  Google Scholar 

  88. Ferrara, J. L., Levine, J. E., Reddy, P. & Holler, E. Graft-versus-host disease. Lancet 373, 1550–1561 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Nordlander, A. et al. Graft-versus-host disease is associated with a lower relapse incidence after hematopoietic stem cell transplantation in patients with acute lymphoblastic leukemia. Biol. Blood Marrow Transplant. 10, 195–203 (2004).

    PubMed  Google Scholar 

  90. Weiden, P. L., Sullivan, K. M., Flournoy, N., Storb, R. & Thomas, E. D. Antileukemic effect of chronic graft-versus-host disease: contribution to improved survival after allogeneic marrow transplantation. N. Engl. J. Med. 304, 1529–1533 (1981).

    CAS  PubMed  Google Scholar 

  91. Hall, E. J. & Giaccia, A. J. Radiobiology for the Radiologist (Lippincott Williams & Wilkins, 2011).

  92. Sridharan, V. et al. Definitive chemoradiation alters the immunologic landscape and immune checkpoints in head and neck cancer. Br. J. Cancer 115, 252–260 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Reits, E. A. et al. Radiation modulates the peptide repertoire, enhances MHC class I expression, and induces successful antitumor immunotherapy. J. Exp. Med. 203, 1259–1271 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Citrin, D. E. & Mitchell, J. B. Mechanisms of normal tissue injury from irradiation. Semin. Radiat. Oncol. 27, 316–324 (2017).

    PubMed  PubMed Central  Google Scholar 

  95. Soussain, C. et al. CNS complications of radiotherapy and chemotherapy. Lancet 374, 1639–1651 (2009).

    CAS  PubMed  Google Scholar 

  96. Rube, C. et al. Dose-dependent induction of transforming growth factor beta (TGF-beta) in the lung tissue of fibrosis-prone mice after thoracic irradiation. Int. J. Radiat. Oncol. Biol. Phys. 47, 1033–1042 (2000).

    CAS  PubMed  Google Scholar 

  97. Simone, C. B. Thoracic radiation normal tissue injury. Semin. Radiat. Oncol. 27, 370–377 (2017).

    PubMed  Google Scholar 

  98. Sprung, C., Forrester, H., Siva, S. & Martin, O. Immunological markers that predict radiation toxicity. Cancer Lett. 368, 191–197 (2015).

    CAS  PubMed  Google Scholar 

  99. Wirsdörfer, F. & Jendrossek, V. The role of lymphocytes in radiotherapy-induced adverse late effects in the lung. Front. Immunol. 7, 591 (2016).

    PubMed  PubMed Central  Google Scholar 

  100. Le Jeune, I. et al. The incidence of cancer in patients with idiopathic pulmonary fibrosis and sarcoidosis in the UK. Respir. Med. 101, 2534–2540 (2007).

    PubMed  Google Scholar 

  101. Chiyo, M. et al. Impact of interstitial lung disease on surgical morbidity and mortality for lung cancer: analyses of short-term and long-term outcomes. J. Thorac. Cardiovasc. Surg. 126, 1141–1146 (2003).

    PubMed  Google Scholar 

  102. Yamaguchi, S. et al. Stereotactic body radiotherapy for lung tumors in patients with subclinical interstitial lung disease: the potential risk of extensive radiation pneumonitis. Lung Cancer 82, 260–265 (2013).

    PubMed  Google Scholar 

  103. Ueki, N. et al. Impact of pretreatment interstitial lung disease on radiation pneumonitis and survival after stereotactic body radiation therapy for lung cancer. J. Thorac Oncol. 10, 116–125 (2015).

    CAS  PubMed  Google Scholar 

  104. Bahig, H. et al. Severe radiation pneumonitis after lung stereotactic ablative radiation therapy in patients with interstitial lung disease. Pract. Radiat. Oncol. 6, 367–374 (2016).

    PubMed  Google Scholar 

  105. Theis, V. S., Sripadam, R., Ramani, V. & Lal, S. Chronic radiation enteritis. Clin. Oncol. 22, 70–83 (2010).

    CAS  Google Scholar 

  106. Ferreira, M., Muls, A., Dearnaley, D. & Andreyev, H. Microbiota and radiation-induced bowel toxicity: lessons from inflammatory bowel disease for the radiation oncologist. Lancet Oncol. 15, e139–e147 (2014).

    PubMed  Google Scholar 

  107. Giaj-Levra, N. et al. Radiotherapy in patients with connective tissue diseases. Lancet Oncol. 17, e109–e117 (2016).

    PubMed  Google Scholar 

  108. Gold, D. G., Miller, R. C., Petersen, I. A. & Osborn, T. G. Radiotherapy for malignancy in patients with scleroderma: the Mayo Clinic experience. Int. J. Radiat. Oncol. Biol. Phys. 67, 559–567 (2007).

    PubMed  Google Scholar 

  109. Pinn, M. E. et al. Systemic lupus erythematosus, radiotherapy, and the risk of acute and chronic toxicity: the Mayo Clinic experience. Int. J. Radiat. Oncol. Biol. Phys. 71, 498–506 (2008).

    PubMed  Google Scholar 

  110. Yu, J. B. et al. Stereotactic body radiation therapy versus intensity-modulated radiation therapy for prostate cancer: comparison of toxicity. J. Clin. Oncol. 32, 1195–1201 (2014).

    PubMed  PubMed Central  Google Scholar 

  111. Yu, J. B. et al. Proton versus intensity-modulated radiotherapy for prostate cancer: patterns of care and early toxicity. J. Natl Cancer Inst. 105, 25–32 (2013).

    CAS  PubMed  Google Scholar 

  112. Nutting, C. M. et al. Parotid-sparing intensity modulated versus conventional radiotherapy in head and neck cancer (PARSPORT): a phase 3 multicentre randomised controlled trial. Lancet Oncol. 12, 127–136 (2011).

    PubMed  PubMed Central  Google Scholar 

  113. Folkert, M. et al. Comparison of local recurrence with conventional and intensity-modulated radiation therapy for primary soft-tissue sarcomas of the extremity. J. Clin. Oncol. 32, 3236–3241 (2014).

    PubMed  PubMed Central  Google Scholar 

  114. Mesia, R. & Taberna, M. HPV-related oropharyngeal carcinoma de-escalation protocols. Lancet Oncol. 18, 704–705 (2017).

    PubMed  Google Scholar 

  115. Bang, A. et al. Multicenter evaluation of the tolerability of combined treatment With PD-1 and CTLA-4 immune checkpoint inhibitors and palliative radiation therapy. Int. J. Radiat. Oncol. Biol. Phys. 98, 344–351 (2017).

    CAS  PubMed  Google Scholar 

  116. Parker, S. M., Zainib, M., Mattes, M. & Amin, N. Multi-institutional report on toxicities from combined radiation and nivolumab [abstract 39]. J. Clin. Oncol. 36 (Suppl. 5), 38–39 (2018).

    Google Scholar 

  117. Luke, J. J. et al. Safety and clinical activity of pembrolizumab and multisite stereotactic body radiotherapy in patients with advanced solid tumors. J. Clin. Oncol. 36, 1611–1618 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. McArthur, H. L. et al. A single-arm, phase II study assessing the efficacy of pembrolizumab (pembro) plus radiotherapy (RT) in metastatic triple negative breast cancer (mTNBC) [abstract 14]. J. Clin. Oncol. 36 (Suppl. 5), 14 (2018).

    Google Scholar 

  119. Barker, C. A. et al. Concurrent radiotherapy and ipilimumab immunotherapy for patients with melanoma. Cancer Immunol. Res. 1, 92–98. (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Liniker, E. et al. Activity and safety of radiotherapy with anti-PD-1 drug therapy in patients with metastatic melanoma. Oncoimmunology 5, e1214788 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Qin, R. et al. Safety and efficacy of radiation therapy in advanced melanoma patients treated with ipilimumab. Int. J. Radiat. Oncol. Biol. Phys. 96, 72–77 (2016).

    CAS  PubMed  Google Scholar 

  122. Aboudaram, A. et al. Concurrent radiotherapy for patients with metastatic melanoma and receiving anti-programmed-death 1 therapy. Melanoma Res. 27, 485–491 (2017).

    CAS  PubMed  Google Scholar 

  123. Nayak, L., Lee, E. Q. & Wen, P. Y. Epidemiology of brain metastases. Curr. Oncol. Rep. 14, 48–54 (2012).

    PubMed  Google Scholar 

  124. Bafaloukos, D. & Gogas, H. The treatment of brain metastases in melanoma patients. Cancer Treat. Rev. 30, 515–520 (2004).

    CAS  PubMed  Google Scholar 

  125. Hodi, F. S. et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 363, 711–723 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Dagogo-Jack, I. et al. A retrospective analysis of the efficacy of pembrolizumab in melanoma patients with brain metastasis. J. Immunother. 40, 108–113 (2017).

    CAS  PubMed  Google Scholar 

  127. Pike, L. R. G. et al. Radiation and PD-1 inhibition: favorable outcomes after brain-directed radiation. Radiother. Oncol. 124, 98–103 (2017).

    CAS  PubMed  Google Scholar 

  128. Nguyen, S. M., Castrellon, A., Vaidis, O. & Johnson, A. E. Stereotactic radiosurgery and ipilimumab versus stereotactic radiosurgery alone in melanoma brain metastases. Cureus 9, e1511 (2017).

    PubMed  PubMed Central  Google Scholar 

  129. Kaidar-Person, O. et al. The incidence of radiation necrosis following stereotactic radiotherapy for melanoma brain metastases: the potential impact of immunotherapy. Anticancer Drugs 28, 669–675 (2017).

    CAS  PubMed  Google Scholar 

  130. Schoenfeld, J. D. et al. Ipilmumab and cranial radiation in metastatic melanoma patients: a case series and review. J. Immunother. Cancer 3, 50 (2015).

    PubMed  PubMed Central  Google Scholar 

  131. Diao, K. et al. Combination ipilimumab and radiosurgery for brain metastases: tumor, edema, and adverse radiation effects. J. Neurosurg. 2018, 1–10 (2018).

    Google Scholar 

  132. Furuse, M., Nonoguchi, N., Kawabata, S., Miyatake, S. & Kuroiwa, T. Delayed brain radiation necrosis: pathological review and new molecular targets for treatment. Med. Mol. Morphol. 48, 183–190 (2015).

    CAS  PubMed  Google Scholar 

  133. Shaw, E. et al. Radiosurgery for the treatment of previously irradiated recurrent primary brain tumors and brain metastases: initial report of radiation therapy oncology group protocol (90–05). Int. J. Radiat. Oncol. Biol. Phys. 34, 647–654 (1996).

    CAS  PubMed  Google Scholar 

  134. Leibel, S. A. & Sheline, G. E. Radiation therapy for neoplasms of the brain. J. Neurosurg. 66, 1–22 (1987).

    CAS  PubMed  Google Scholar 

  135. Verma, N., Cowperthwaite, M. C., Burnett, M. G. & Markey, M. K. Differentiating tumor recurrence from treatment necrosis: a review of neuro-oncologic imaging strategies. Neuro Oncol. 15, 515–534 (2013).

    PubMed  PubMed Central  Google Scholar 

  136. Fang, P. et al. Radiation necrosis with stereotactic radiosurgery combined with CTLA-4 blockade and PD-1 inhibition for treatment of intracranial disease in metastatic melanoma. J. Neurooncol 133, 595–602 (2017).

    CAS  PubMed  Google Scholar 

  137. Kohutek, Z. A. et al. Long-term risk of radionecrosis and imaging changes after stereotactic radiosurgery for brain metastases. J. Neurooncol 125, 149–156 (2015).

    PubMed  PubMed Central  Google Scholar 

  138. Martin, A. M. et al. Immunotherapy and symptomatic radiation necrosis in patients with brain metastases treated with stereotactic radiation. JAMA Oncol. https://doi.org/10.1001/jamaoncol.2017.3993 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  139. Skrepnik, T., Sundararajan, S., Cui, H. & Stea, B. Improved time to disease progression in the brain in patients with melanoma brain metastases treated with concurrent delivery of radiosurgery and ipilimumab. Oncoimmunology 6, e1283461 (2017).

    PubMed  PubMed Central  Google Scholar 

  140. Colaco, R. J., Martin, P., Kluger, H. M., Yu, J. B. & Chiang, V. L. Does immunotherapy increase the rate of radiation necrosis after radiosurgical treatment of brain metastases? J. Neurosurg. 125, 17–23 (2016).

    CAS  PubMed  Google Scholar 

  141. Patel, K. R. et al. Ipilimumab and stereotactic radiosurgery versus stereotactic radiosurgery alone for newly diagnosed melanoma brain metastases. Am. J. Clin. Oncol. 40, 444–450 (2017).

    CAS  PubMed  Google Scholar 

  142. Miller, J. A. et al. Association between radiation necrosis and tumor biology after stereotactic radiosurgery for brain metastasis. Int. J. Radiat. Oncol. 96, 1060–1069 (2016).

    Google Scholar 

  143. Williams, N. L. et al. Phase 1 study of ipilimumab combined with whole brain radiation therapy or radiosurgery for melanoma patients with brain metastases. Int. J. Radiat. Oncol. Biol. Phys. 99, 22–30 (2017).

    CAS  PubMed  Google Scholar 

  144. Brahmer, J. et al. Nivolumab versus docetaxel in advanced squamous-cell non–small-cell lung cancer. N. Engl. J. Med. 373, 123–135 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. Herbst, R. S. et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet 387, 1540–1550 (2016).

    CAS  PubMed  Google Scholar 

  146. Reck, M. et al. Pembrolizumab versus chemotherapy for PD-L1–positive non–small-cell lung cancer. N. Engl. J. Med. 375, 1823–1833 (2016).

    CAS  PubMed  Google Scholar 

  147. Fehrenbacher, L. et al. Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial. Lancet 387, 1837–1846 (2016).

    CAS  PubMed  Google Scholar 

  148. Garon, E. B. et al. Pembrolizumab for the treatment of non–small-cell lung cancer. N. Engl. J. Med. 372, 2018–2028 (2015).

    PubMed  Google Scholar 

  149. Kim, M., Schrag, D., Li, L. & Chen, A. B. Predictors of radiation therapy (RT) use among medicare patients with metastatic non-small cell lung cancer (NSCLC) [abstract 124]. J Clin Oncol 33 (suppl. 29), 124 (2015).

    Google Scholar 

  150. Koshy, M. et al. Prevalence and predictors of inappropriate delivery of palliative thoracic radiotherapy for metastatic lung cancer. J. Natl Cancer Inst. 107, djv278 (2015).

    PubMed  PubMed Central  Google Scholar 

  151. Lu, C. S. & Liu, J. H. Pneumonitis in cancer patients receiving anti-PD-1 and radiotherapies: three case reports. Medicine 96, e5747 (2017).

    PubMed  PubMed Central  Google Scholar 

  152. Shaverdian, N. et al. Previous radiotherapy and the clinical activity and toxicity of pembrolizumab in the treatment of non-small-cell lung cancer: a secondary analysis of the KEYNOTE-001 phase 1 trial. Lancet Oncol. 18, 895–903 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. Antonia, S. J. et al. Durvalumab after chemoradiotherapy in stage III non–small-cell lung cancer. N. Engl. J. Med. 377, 1919–1929 (2017).

    CAS  PubMed  Google Scholar 

  154. Samstein, R. et al. Partial tumor irradiation in a murine model is sufficient for tumor control via activation of an antitumor immune response. Int. J. Radiat. Oncol. Biol. Phys. 99, E616–E617 (2017).

    Google Scholar 

  155. Marusyk, A., Almendro, V. & Polyak, K. Intra-tumour heterogeneity: a looking glass for cancer? Nat. Rev. Cancer 12, 323–334 (2012).

    CAS  PubMed  Google Scholar 

  156. Gerlinger, M. et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N. Engl. J. Med. 366, 883–892 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  157. Patel, A. P. et al. Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma. Science 344, 1396–1401 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  158. Choudhury, A. et al. MRE11 expression is predictive of cause-specific survival following radical radiotherapy for muscle-invasive bladder cancer. Cancer Res. 70, 7017–7027 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  159. Mahoney, K. M., Rennert, P. D. & Freeman, G. J. Combination cancer immunotherapy and new immunomodulatory targets. Nat. Rev. Drug Discov. 14, 561–584 (2015).

    CAS  PubMed  Google Scholar 

  160. Strojan, P. et al. Treatment of late sequelae after radiotherapy for head and neck cancer. Cancer Treat. Rev. 59, 79–92 (2017).

    PubMed  PubMed Central  Google Scholar 

  161. Siddiqui, F. & Movsas, B. Management of radiation toxicity in head and neck cancers. Semin. Radiat. Oncol. 27, 340–349 (2017).

    PubMed  Google Scholar 

  162. Nicholas, S. et al. Pelvic radiation and normal tissue toxicity. Semin. Radiat. Oncol. 27, 358–369 (2017).

    PubMed  Google Scholar 

  163. Munoz-Schuffenegger, P., Ng, S. & Dawson, L. A. Radiation-induced liver toxicity. Semin. Radiat. Oncol. 27, 350–357 (2017).

    PubMed  Google Scholar 

  164. Kwon, E. D. et al. Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol. 15, 700–712 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors thank T. Hong, N. Depauw, and H. Paganetti for assistance with preparing figures 1 and 2 and D. N. Cagney for helpful discussions.

Reviewer information

Nature Reviews Clinical Oncology thanks J. Chang, S. Chmura, and T. Illidge for their contribution to the peer review of this work.

Author information

Authors and Affiliations

Authors

Contributions

All authors made a substantial contribution to all aspects of the preparation of this manuscript.

Corresponding author

Correspondence to Jay S. Loeffler.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hwang, W.L., Pike, L.R.G., Royce, T.J. et al. Safety of combining radiotherapy with immune-checkpoint inhibition. Nat Rev Clin Oncol 15, 477–494 (2018). https://doi.org/10.1038/s41571-018-0046-7

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41571-018-0046-7

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing