Review Reports

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

1. The absence of broader molecular profiling is a major limitation.
Only EGFR, ALK, and PD-L1 were tested. Given the exceptional outcome, one would expect at least next-generation sequencing (NGS) to rule out other actionable drivers (e.g., ROS1, RET, MET, KRAS, BRAF) or tumor mutational burden (TMB). The authors mention this in the limitations, but it undermines the claim of “molecularly unfavorable” – we simply don’t know if a hidden driver explains the response.

2. Neurocognitive assessment lacks formal testing.
The authors repeatedly note “no clinically apparent neurocognitive deterioration” after conventional WBRT without hippocampal sparing. Without serial neuropsychological evaluations (e.g., HVLT-R, COWA), this claim is too strong. Clinicians often miss subtle cognitive decline. The discussion should be rephrased to state what was not observed rather than implying preserved function.

3. The radiation doses for SRS are unusually low.
The first brain metastasis received 10 Gy single fraction; the second received 8 Gy. Both are below standard ablative doses (typically 18–24 Gy for lesions <2 cm). The authors justify this by lesion size and edema, but this needs more explanation. Could the low dose have contributed to eventual progression of the occipital lesion? The case does not clarify why dose escalation was not pursued.

4. The role of adjuvant immunotherapy is under-discussed.
The patient received six cycles of pembrolizumab plus chemotherapy after lobectomy. Even with PD-L1 <1%, some patients derive benefit. Could the durable intracranial control partly reflect a delayed systemic immune effect? The authors focus heavily on radiotherapy but give minimal attention to the potential contribution of immune checkpoint inhibition. This imbalance should be corrected.

5. The claim of “exceptional” outcome lacks comparative context.
Long-term survival (>5 years) in NSCLC patients with brain metastases, even with unfavorable biomarkers, is rare but has been reported. The authors do not cite any series or registry data to benchmark this case. A brief comparison with expected survival in similar molecular subgroups (e.g., from large retrospective cohorts) would strengthen the argument.

Author Response

Thank you for your review. Please find attached our response. 

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

This study demonstrates long-term intracranial disease control and maintenance of a good quality of life for over five years in non-small cell lung cancer (EGFR/ALK wild-type, PD-L1 < 1%), a disease with an extremely poor prognosis for which no effective targeted drugs exist. The treatment process, which adaptively switched between stereotactic radiotherapy, whole-brain irradiation, and neurosurgical resection according to the stage and condition of metastasis, serves as a reference for multidisciplinary treatment of complex brain metastases. Some revisions are needed for publication.

・The assessment of gene mutations is limited to the 2020 criteria (EGFR, ALK, PD-L1). To understand why this patient achieved exceptional long-term survival, is it possible to add data on the presence of other mutations such as KRAS and MET using past surgical specimens (primary tumor in 2020 and brain metastases in 2024)?

・Since surgery to remove brain metastases was performed in 2024, there is an opportunity to directly compare it with the tissue from the primary lung tumor in 2020. Were there any characteristic pathological findings that contributed to long-term survival?

・While it is stated that no cognitive decline was observed after whole-brain irradiation without hippocampal avoidance, this is a qualitative assessment based on physician observation. Even though hippocampal avoidance was not intended, there is a lack of dose-volume histogram data showing the total radiation dose actually delivered to the hippocampus. Please provide detailed cumulative dose distributions for stereotactic radiotherapy and whole-brain irradiation.

Author Response

Thank you for your review. Please find attached our response. 

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The manuscript has been well revised and is recommended for publication.