Review Article | Published:

Safety of combining radiotherapy with immune-checkpoint inhibition

Nature Reviews Clinical Oncologyvolume 15pages477494 (2018) | Download Citation


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.

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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.

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Author notes

  1. These authors contributed equally: William L. Hwang, Luke R. G. Pike.


  1. Harvard Radiation Oncology Program, Harvard Medical School, Boston, MA, USA

    • William L. Hwang
    • , Luke R. G. Pike
    • , Trevor J. Royce
    •  & Brandon A. Mahal
  2. Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA, USA

    • William L. Hwang
    • , Luke R. G. Pike
    • , Trevor J. Royce
    • , Brandon A. Mahal
    •  & Jay S. Loeffler
  3. Department of Neurosurgery, Massachusetts General Hospital, Boston, MA, USA

    • Jay S. Loeffler


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

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The authors declare no competing interests.

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Correspondence to Jay S. Loeffler.

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