Among scenarios where immune checkpoint inhibitors (ICIs) might be combined, particular caution is needed in the setting of brain metastases, according to authors of a recent clinical review.
While evidence to date is mixed, some studies do suggest that adding ICIs to high-dose stereotactic intracranial radiotherapy for brain metastases might increase the risk of treatment-related brain necrosis, the authors said.
By contrast, the balance of evidence suggests ICIs can be safely combined with palliative radiotherapy without site-specific increases in adverse events, they added.
Likewise, in patients with non–small-cell lung cancer, ICIs do not appear to increase incidence of grade 3 or greater pneumonitis when given after definitive chemoradiotherapy, in both retrospective and prospective investigations.
Nevertheless, the addition of ICIs to radiotherapy requires careful further study because of the potential for increased type or severity of toxicities, including the immune-related adverse events associated with ICIs, wrote corresponding author Jay S. Loeffler, MD, of Massachusetts General Hospital, Boston, and his colleagues.
“Caution is warranted when combining radiotherapy and ICI, especially with intracranial radiotherapy,” the researchers wrote. Their report is in.
Some studies have indicated a higher rate of treatment-associated brain necrosis when ICIs are combined with intracranial radiotherapy, while others have shown no such trend, the authors said.
In one single-institution experience involving 180 patients with brain metastases undergoing stereotactic radiotherapy, incidence of treatment-associated brain necrosis was significantly higher in patients receiving an ICI, with an odds ratio of 2.4 (95% confidence interval, 1.06-5.44; P = .03).
Similarly, a retrospective single institution 480-patient study showed an incidence of treatment-associated brain necrosis of 20% for ICIs plus stereotactic radiotherapy versus 7% for radiotherapy alone (P less than .001), but substantial differences in baseline characteristics between groups limited the strength of the study’s conclusions, according to the researchers.
Increased risk is primarily in the form of asymptomatic or minimally symptomatic episodes in some series, the authors noted. A retrospective, 54-patient report showed a rate of treatment-associated brain necrosis of 30% when ICIs were combined with stereotactic radiotherapy, versus 21% for radiotherapy alone (P = .08), but the incidence of symptomatic cases was 15% in both groups, they noted.
“Intriguingly, the findings of several studies have demonstrated an association between [treatment-associated brain necrosis] and improved survival outcomes in patients with melanoma brain metastases that is similar to the independent observations of an analogous relationship between risk of [immune-related adverse events] in general and responsiveness to ICI,” the researchers wrote.
Most of the Food and Drug Administration–approved indications for ICIs are in the metastatic setting, where palliative radiotherapy is frequently important, the authors noted.
In two retrospective studies of patients with metastatic cancers receiving palliative radiotherapy with ICIs, there was a lack of clear association between the irradiated site and specific immune-related adverse events; that lack of association suggests that any toxicities arising from interactions between palliative radiotherapy and ICIs are mainly systemic, rather than local, the authors wrote.
Several retrospective series in advanced-stage melanoma patients have suggested that palliative radiotherapy plus ICIs is safe and does not significantly increase incidence of immune-related adverse events. However, findings from one series showed a correlation between both the ICI and radiotherapy dose given and the incidence of immune-related adverse events.
Prospective studies will be essential to optimize the balance between disease control and risk of morbidity associated with ICIs and radiotherapy combinations, the authors concluded.
The researchers declared no competing interests related to their review article.
SOURCE: Hwang WL, et al. Nat Rev Clin Oncol. 2018 .