A balancing ACT: maximizing the benefits of appropriate brain radiation therapy—authors’ reply

We thank Divya Yerramilli and colleagues¹ for their interest in our study² on patients newly diagnosed with first-time brain metastases and appreciate the opportunity to address their concerns.

Our prospective study² reflects treatment selection during the study period from 2017 to 2021 in the participating study centers. In general, patient selection was compliant with current international and Norwegian guideline criteria. As such, the different treatment groups clearly represent distinct prognostic groups, with particular relevance to the surgery group. However, almost 50% of the patients included in the study died within 6 months after diagnosis of brain metastases. Consequently, a large proportion did not live long enough to achieve substantial benefits from anticancer treatment (ACT), as shown by the patient-reported outcomes (PRO) in our study. We identified ECOG 2 as a risk factor in this respect, calling for thorough considerations by clinicians regarding ACT for patients with brain metastases. As we also emphasized in our article, factors such as extracranial disease status, number of brain metastases, and potential for further systemic treatment are additional important prognostic factors to be included in treatment considerations. A patient with ECOG 2 and a single brain metastasis and no extracranial disease might benefit from obtaining intracranial control through surgery or stereotactic radiotherapy (SRT). Conversely, a patient with ECOG 2 having more than four brain metastases and progressive extracranial disease will most likely not benefit from any ACT. One may speculate that a proportion of patients in our study classified as ECOG 2 in reality were ECOG 3, illustrating the importance of proper classification of patients.

The randomized QUARTZ trial³ demonstrated equally short survival and quality of life after best supportive care (BSC) alone or BSC plus whole brain radiotherapy (WBRT) in patients with non-small cell lung cancer and brain metastases who were not candidates for surgery or SRT. An observational study like ours cannot directly compare different treatment modalities, but our data supports the findings in the QUARTZ trial, also in primary cancers other than lung cancer.

The QUARTZ study demonstrated that WBRT did not reduce the use of corticosteroids, weakening the argument for ACT to reduce steroid side effects in patients with short expected survival. We would argue that ACT probably has a stronger negative impact on quality of life than corticosteroids in the last months of life.

We agree that improvements in systemic therapy may change the prospects of achieving intracranial and extracranial disease control in patients with brain metastases, potentially changing brain metastasis treatment considerations. Nevertheless, a patient-centered approach implies that, more often than not, patients with ECOG 2 diagnosed with brain metastases are at high risk of short survival and futile ACT. We agree with Yerramilli and colleagues that we must think before we ACT – and ECOG 2 should make us think even more.

Contributors

Olav E. Yri, Stein Kaasa. Both authors contributed to the writing of the letter.

Declaration of interests

OEY and SK have received funding of study/research infrastructure by the Norwegian South-East Regional Health Authority and The Norwegian Cancer Society.