Ablative Radiation May Be Feasible For Patients With Oligometastases

Author: By Lynda Williams, Senior medwireNews Reporter 

medwireNews: Stereotactic body radiotherapy (SBRT) does not appear to be associated with dose-limiting toxicity (DLT) when used with curative intent for patients with three or four metastases or with two metastases close together, indicates early research. 

While SBRT has been increasingly used for the treatment of oligometastases, there is little prospective safety data and the delivery is “technically challenging” because of the cumulative radiation doses to the surrounding organs and the need to consider prior radiotherapy treatment, explain Steven Chmura, from the University of Chicago in Illinois, USA, and fellow NRG-BR001 trial investigators. 

Their phase I study included 39 North American patients who received an SBRT protocol – based on dosing used for single metastases – for the treatment of three or four metastases or for two metastases within 5 cm of each other at one of seven anatomic locations. 

Specifically, patients received an initial dose of 50 Gy in five fractions to the central lung or mediastinal/cervical lymph nodes, or 45 Gy in three fractions to the peripheral lung, abdomen/pelvis or liver, or 30 Gy in three fractions to the bone/osseous and spinal/paraspinal regions. 

The primary endpoint of DLT was assessed in 20 men and 15 women, aged a median 63.1 years, with prostate cancer (37.1%), breast cancer (34.3%) or non-small-cell lung cancer (28.6%). The majority (66.0%) of these patients had three or four metastases and 60.0% of the group had previously undergone radiation to other sites. 

“Despite the complexity of the treatment protocol, SBRT was delivered per protocol or with acceptable variations in all but 1 case”, and there were no DLTs at any of the anatomic locations, the researchers report in JAMA Oncology.

“Given this, the initial starting dose is the recommended SBRT dose for each metastatic site,” Steven Chmura and co-authors say, adding that these protocols are now being used for ongoing trials, including the phase II–III NRG-BR002 trial for patients with metastatic breast cancer. 

Nevertheless, there were 45 grade 3 and five grade 4 adverse events (AEs) reported in 18 patients, 36% of which were considered possibly, probably or definitely related to SBRT. These consisted of 16 grade 3 and two grade 4 AEs in nine patients, 12 of which occurred after more than 180 days. 

Eight AEs were “determined to be mechanistically related to protocol therapy”, the investigators say, including a case of grade 3 pneumonitis at day 125 in a breast cancer patient and a grade 3 gastric ulcer at day 131 in a lung cancer patient. 

The remaining protocol-related AEs included bone pain, pulmonary fibrosis, and spinal and humeral fractures, as well as two grade 3 late AEs of bronchial stenosis and bronchial fistula, both of which occurred in patients treated at the central lung or hilar regions. 

This gave an 18-month and 24-month cumulative rate of grade 3–4 late treatment-related AEs of 17% and 20%, respectively, the researchers say. 

After a median 23.9 months of follow-up, 15 of the 39 assessed patients had died from metastatic disease. Median overall survival was unreached and the 2-year rate was 57%. 

Writing in a linked Editor’s note, Charles Thomas Jr, from Oregon Health Sciences University in Portland, USA, says that the NRG-BR001 trial findings both “provide evidence to guide patient care” and act as a “framework” for further trials.

However, he cautions that “despite the results endorsing the working hypothesis that short-term toxicity was acceptable, it is clear that longer follow-up is necessary in these patients”, especially among those who may benefit from recent advances in systemic therapies for metastatic disease.

Charles Thomas Jr concludes: “Because these toxic effects, particularly bone fractions and pulmonary toxicity, can compromise daily quality of life, we strongly believe that clinicians must be sure to caution patients about the specific normal tissue toxicity profile that can occur depending on the anatomic site that is to be targeted with SBRT.”

References 

Chmura S, Winter KA, Robinson C, et al. Evaluation of safety of stereotactic body radiotherapy for the treatment of patients with multiple metastases. Findings from the NRG-BR001 phase I trial. JAMA Oncol; Advance online publication 22 April 2021. doi:10.1001/jamaoncol.2021.0687

Thomas CR Jr. Radiation-induced toxicity in the era of stereotactic body radiation therapy – Lessons from NRG-BR001. JAMA Oncol; Advance online publication 22 April 2021. doi:10.1001/jamaoncol.2021.0677