T-DM1/Brain SRS May Increase Risk of Radionecrosis in Breast Cancer

"More prospective large cohorts are required to systematically report details on radiation therapy intent, volumes, doses, and techniques to further enhance our understanding of this combination treatment," according to the authors of a meta-analysis published in Radiotherapy and Oncology.

Antibody-drug conjugate ado-trastuzumab emtansine (Kadcyla; T-DM1) showed an acceptable safety profile but appeared to increase rates of symptomatic radionecrosis when combined with stereotactic radiosurgery (SRS) vs SRS alone for the locoregional treatment of non-metastatic breast cancer, according to findings from a meta-analysis published in Radiotherapy and Oncology.

Across 5 retrospective single-institution studies that reported toxicities related to intracranial irradiation, the pooled incidence of grade 2 or higher radionecrosis was 37%, and the incidence of grade 3 or higher radionecrosis was 17%. Notably, there was significant heterogeneity in the incidence of this toxicity across the studies (I2, 72.9%).

The corresponding pooled incidences of radiation-related pneumonitis were 1% and less than 1%, respectively, across 3 studies conducted in the adjuvant setting. In contrast to the radionecrosis data, there was very low heterogeneity in these frequencies (I2, 0%). Moreover, the pooled incidence of grade 2 or higher and grade 3 or higher radiation-related skin toxicity was 32% and 1%, respectively, across 3 published studies. There was a low level of heterogeneity in these data (I2, 0%), as well.

“In our study, we found a pooled incidence…[that] is higher than the reported incidence…after brain stereotactic radiosurgery [SRS] alone,” the investigators wrote. “This highlights the potential increased risk associated with [T-DM1 plus radiotherapy]. Therefore, caution is advised when using this combination for the treatment of intracranial disease.

“However, due to the lack of robust data, clear recommendations cannot be made for the treatment of extracranial metastasis. In the context of locoregional treatment for non-metastatic disease, the toxicity associated with the combination of T-DM1 and [radiation therapy] was found to be low, with minimal acute skin effects and radiation-related pneumonitis.”

This systematic review and meta-analysis included data from 9 articles found through the PUBMED/MedLine, Embase, and Cochrane databases between January 2010 and September 2022. The analysis included 1813 patients. Median patient ages ranged from 35 to 56 years, and median follow-up times ranged from 3 to 57 months.

The analysis of treatment-related toxicity for intracranial irradiation included 5 studies with populations ranging from 7 to 28 patients and a median enrolled population of 16. Of these studies, 3 were conducted in the United States, and 1 each was conducted in France and Canada. In 3 of these studies, diagnosis of radionecrosis was either pathological or radiological, and 2 did not specify how diagnosis occurred. All studies categorized the timing of brain SRS and administration of T-DM1 as sequential or concomitant.

The 3 adjuvant setting studies that reported on radiation pneumonitis consisted of a single-arm phase 2 study with 116 enrolled patients, a randomized phase 2 study with 239 patients, and a randomized phase 3 trial with 624 patients. The 3 that reported on radiation-related skin toxicity consisted of a retrospective observational study with 14 patients, a randomized phase 2 study with 239 patients, and a randomized phase 3 trial with 624 patients.

“There is a need for international consensus recommendations on the safety of combining T-DM1 and radiation therapy for breast cancer,” the investigators concluded. “Additionally, more prospective large cohorts are required to systematically report details on radiation therapy intent, volumes, doses, and techniques to further enhance our understanding of this combination treatment.”

Reference

Salvestrini V, Kim K, Caini S, et al. Safety profile of trastuzumab-emtansine (T-DM1) with concurrent radiation therapy: a systematic review and meta-analysis. Radiother Oncol. Published online July 10, 2023. doi:10.1016/j.radonc.2023.109805