Combination of Radiotherapy and Immunotherapy in the Clinic
Concepts for Clinical Combinations
Possible clinical trial concepts mostly aim at improving local and systemic control in metastatic cancer patients. Taking into account the possible abscopal effect achieved with the combination, radiotherapy of 1 of the metastatic lesions combined with immunotherapy might prolong survival. The concept of radiation achieving an in situ vaccine effect gave rise to the idea of continuing immunotherapy after the development of resistance and progression with radiotherapy to 1 of the progressing lesions. Combining immunotherapy with curative radiotherapy has been discussed for stereotactic ablative radiotherapy of early stage lung cancer in patients carrying a substantial risk for systemic relapse.
Questions and Challenges
There are intense discussions about the dose and fractionation of radiotherapy combined with immunotherapy. Clinically, multiple radiation schedules are tested for different cancer entities [93]. For the combination with immune checkpoint inhibition, preclinical data suggest an advantage of hypofractionated over single dose regimens [69]. The activation of dendritic cells has been shown for hypofractionated and normofractionated radiation regimes [94]. However, the ideal dose and fractionation has not yet been determined [51, 95]. Preclinical data and available case reports also suggest a superiority of simultaneous regimens or irradiation after the start of immune checkpoint inhibition over a schedule starting with irradiation [63, 69, 96]. The data on the introduction of immunotherapy into normofractionated regimens encompassing adjuvant lymphatic regions applied in neoadjuvant or adjuvant settings and for primary radio(-chemo) therapy is scarce. In addition, the optimal radiation dose, fractionation, and scheduling might differ depending on the immunotherapeutic strategy investigated.
Conclusion
Immunotherapy is being established as a “fourth pillar” of cancer therapy and is entering the clinic in multiple tumour entities. There is a strong theoretical and preclinical rationale for different immunotherapy strategies stating that the combination of immunotherapy with radiation might be beneficial (Fig. 1). Multiple combination strategies have entered clinical trials (Table 1). However, the details of optimal combination regimens are still under investigation.
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