BACKGROUND: Up to 30% patients newly diagnosed with advanced non-small cell lung cancer (NSCLC) present with brain metastases. In the absence of oncogenic addiction, first-line immunotherapy, alone or in combination with chemotherapy, is the current standard of care. This review aims to synthesize the available data regarding the efficacy of immunotherapy in these patients, and to discuss the possibility of its being coordinated with local treatments such as radiotherapy.
BACKGROUND: NSCLC patients with brain metastases appear to have survival benefits with immunotherapy similar to those of NSCLC patients without brain metastases. However, this finding is based on mainly prospective studies having included highly selected patients with pre-treated and stable brain metastases. Several retrospective studies and two prospective single-arm studies have confirmed the intracranial efficacy of immunotherapy, either alone or in combination with chemotherapy.
CONCLUSIONS: The indications and optimal timing for cerebral radiotherapy remain subjects of debate. To date, there exists no randomized study assessing the addition of brain radiotherapy to first-line immunotherapy. That said, a recent meta-analysis showed increased intracerebral response when radiotherapy complemented immunotherapy.
CONCLUSIONS: For NSCLC patients with brain metastases, the available data suggest a clear benefit of first-line immunotherapy, whether alone or combined with chemotherapy. However, most of these data are drawn from retrospective, non-randomized studies with small sample sizes.

Palliative radiotherapy is used to alleviate cancer-related symptoms. Symptomatic responses to palliative radiotherapy may however take several weeks, meaning that patients need to survive long enough to derive a real benefit. Oncologists can be optimistic when estimating survival for patients with advanced cancer and as a consequence some patients receiving palliative radiotherapy die before experiencing any gain. Models of patient survival have limited accuracy, particularly for predicting whether patients will die within the next 30 days. Dedicated rapid access palliative radiotherapy clinics, in which patients are assessed, simulated and treated on the same day, reduce the number of patient visits to the radiation oncology department and hence the burden on the patient as well as costs. Teleconsultation and advanced practice nurses can play a crucial role in providing rapid access to palliative radiotherapy in a dedicated palliative radiotherapy service. Single-fraction palliative radiotherapy should be offered to eligible patients if they are able to attend treatment and could potentially benefit from symptom palliation, irrespective of predicted life expectancy. Technical and organizational innovations have been proposed in order to dispense with the computed tomography scanner by carrying out the dosimetry on a recent diagnostic scanner or a magnetic resonance imaging scanner with integrated linear acceleration system. Stereotactic body radiation therapy makes it possible to envisage greater and more lasting analgesic benefits in patients with painful bone metastasis and good prognosis. Flash radiotherapy remains at the preclinical stage.

Although tyrosine kinase inhibitors (TKI) have revolutionized the treatment of anaplastic lymphoma kinase rearranged non-small cell lung cancer (ALKr-NSCLC), radiotherapy (RT) still plays an essential role for treatment of both intracranial and extracranial metastases, particularly for patients experienced a TKI-failure. We reported the case of a 38-year-old woman with metastatic ALKr-NSCLC who received whole-brain radiotherapy (RT) for multiple brain metastases (BMs), initially. After RT, alectinib was initiated and the patient had a good clinico-radiological response in both intracranial and extracranial regions. However, intracranial progression was developed and, stereotactic radiosurgery (SRS) was applied to the four progressed BMs. Two months after SRS, all BMs disappeared. While patient was using alectinib, a recurrent lung lesion, a hilar lymph node and bone metastasis were detected. Stereotactic body radiotherapy (SBRT) was applied to all metastatic sites and, alectinib was continued again. Three months after SBRT, a complete response was obtained. She has been alive with the initial systemic therapy agent for more than 4years without evidence of neither disease nor toxicity. SRS/SBRT may eradicate the TKI-resistant tumoral clones and it may prevent switching the systemic therapy, even if there is a failure.

The management of patients with brain oligometastases is complex and relies on specific reasoning compared to extracranial oligometastases. The levels of evidence are still low because patients with brain oligometastases are frequently excluded from randomized clinical trials. Stereotactic radiotherapy should be preferred in this indication over whole brain irradiation, both for patients with metastases in place and for those who have undergone surgery. The decision of local treatment and its timing must be a multidisciplinary reflection taking into account the histological and molecular characteristics of the tumor as well as the intracranial efficacy of the prescribed systemic treatments. Great caution must be observed when using stereotactic radiotherapy and concomitant systemic treatments because interactions are still poorly documented. We present the recommendations of the French society of radiation oncology on the management of brain oligometastatic patients with radiotherapy.

Whole brain reirradiation for the treatment of multiple brain metastases has shown promising results. However, concerns remain over the possible neurotoxic effects of the cumulative dose as well as the questionable radiosensitivity of recurrent metastases. A second reirradiation of the whole brain is ordinarily performed in our department for palliative purposes in patients presenting with multiple metastatic brain progression. For this study, an investigational third whole brain reirradiation has been administered to highly selected patients to obtain disease control and delay progression. Clinical outcomes and neurological toxicity were also evaluated.

OBJECTIVE: Despite significant advances that have been made in management of metastatic melanoma with immune checkpoint therapy, optimal timing of combination immune checkpoint therapy and stereotactic radiosurgery is unknown. We have reported toxicity and efficiency outcomes of patients treated with concurrent immune checkpoint therapy and stereotactic radiosurgery.
METHODS: From January 2014 to December 2016, we analyzed 62 consecutive patients presenting 296 melanoma brain metastases, treated with gamma-knife and receiving concurrent immune checkpoint therapy with anti-CTLA4 or anti-PD1 within the 12 weeks of SRS procedure. Median follow-up time was 18 months (mo) (13-22). Minimal median dose delivered was 18 gray (Gy), with a median volume per lesion of 0.219 cm3.
RESULTS: The 1-year control rate per irradiated lesion was 89% (CI 95%: 80.41-98.97). Twenty-seven patients (43.5%) developed distant brain metastases after a median time of 7.6 months (CI 95% 1.8-13.3) after gamma-knife. In multivariate analysis, positive predictive factors for intracranial tumor control were: delay since the initiation of immunotherapy exceeding 2 months before gamma-knife procedure (P=0.003) and use of anti-PD1 (P=0.006). Median overall survival (OS) was 14 months (CI 95%: 11-NR). Total irradiated tumor volume<2.1 cm3 was a positive predictive factor for overall survival (P=0.003). Ten patients (16.13%) had adverse events following irradiation, with four grade≥3. Predictive factors of all grade toxicity were: female gender (P=0.001) and previous treatment with MAPK (P=0.05).
CONCLUSIONS: A long duration of immune checkpoint therapy before stereotactic radiosurgery might improve intracranial tumor control, but this relationship and its ideal timing need to be assessed in prospective trials.

OBJECTIVE: Stereotactic radiotherapy (SRT) was widely used in brain metastases (BM), especially in oligometastases. It is imperative to develop a new prognostic score to predict the overall survival (OS) of brain metastases based on prognostic factors for specific primary tumors.
METHODS: One hundred and ninety-seven patients were involved in the training cohort to develop a new prognostic score to predict the overall survival (OS) of brain metastases for specific primary tumors. Independent prognostic factors were confirmed using a Cox regression model. The score was developed based on clinical prognostic factors of OS with Cox proportional hazards model. The result was validated in another cohort with 56 participants to evaluate the performance of the score.
RESULTS: One hundred and ninety-seven patients with 329 brain metastases received SRT. For NSCLC, the significant prognostic factors were extracranial metastases, target therapy and number of brain metastases. For gastrointestinal cancer, the significant prognostic factors were target therapy and number of brain metastases.
CONCLUSIONS: The prognostic factors scores were varied by the histologic types which can be used to efficiently stratify for selected patients with brain-metastasis.

OBJECTIVE: The aim of the present retrospective study was to report outcomes after hypofractionated stereotactic radiotherapy (HSRT) for resected brain metastases (BM).
METHODS: We reviewed results of patients with resected BM treated with postoperative HSRT (3×7.7Gy to the prescription isodose 70%) between May 2013 and June 2020. Local control (LC), distant brain control (DBC), overall survival (OS), leptomeningeal disease relapse (LMDR), and radiation necrosis (RN) occurrence were reported.
RESULTS: Twenty-two patients with 23 brain cavities were included. Karnofsky Performance status (KPS) was≥70 in 77.3%. Median preoperative diameter was 37mm [21.0-75.0] and median planning target volume (PTV) was 23 cm3 [9.9-61.6]. Median time from surgery to SRT was 69 days [7-101] and 48% of patients had a local relapse on pre-SRT imaging. Median follow-up was 17.5 months [1.6-95.9]. One and two-year LC rates were 60.9 and 52.2% respectively. One and 2-year DBC rates were 45.5 and 40.9%. Median OS was 16.5 months. Four patients (18.2%) presented LMDR during follow-up. RN occurred in 6 patients (27.2%). Three factors were associated with OS: ECOG-PS (P=0.009), KPS (P=0.04), cystic or solid nature of the metastasis before surgery (P=0.037). Several factors were related to RN occurrence: PTV diameter and volume, Normal brain V21, V21 and V24 isodoses volumes.
CONCLUSIONS: HSRT is the most widely used scheme for larger brain cavities after surgery. The optimal dose and scheme remain to be defined as well as the optimal delay between postoperative SRT and surgery. Dose escalation may be necessary, especially in case of subtotal resection.

OBJECTIVE: Between 10 and 40% of patients with cancer will develop one or more brain metastases (BMs). Stereotactic radiotherapy (SRT) is part of the therapeutic arsenal for the treatment of de novo or recurrent BM. Its main interest is to delay whole brain radiation therapy (WBRT), which may cause cognitive toxicity. However, SRT is not exempt from long-term toxicity, and the most widely known SRT is radionecrosis (RN). The objective of this study was to analyze the occurrence of RN per BM and per patient.
METHODS: Between 2010 and 2020, data from 184 patients treated for 915 BMs by two to six SRT sessions for local or distant brain recurrence without previous or intercurrent WBRT were retrospectively reviewed. RN was examined on trimestral follow-up MRI and potentially confirmed by surgery or nuclear medicine. For each BM and SRT session plan, summation V12Gy, V14Gy, V21Gy and V23Gy isodoses were collected. Volumes of intersections were created between the 12Gy isodose at the first SRT and the 18Gy isodose of the following SRT (V18-12Gy).
RESULTS: At the end of follow-up, 23.0% of patients presented RN, and 6.3% of BM presented RN. Median follow-up of BM was 13.3 months (95%CI 18.3-20.8). The median interval between BM irradiation and RN was 8.7 months (95% CI 9.2-14.7). Six-, 12- and 24-month RN-free survival rates per BM were 75%, 54% and 29%, respectively. The median RN-free survival per patient was 15.3 months (95% CI 13.6-18.1). In multivariate analysis, the occurrence of RN per BM was statistically associated with local reirradiation (P<0.001) and the number of SRTs (P<0.001). In univariate analysis, the occurrence of RN per patient was statistically associated with the sum of all V18-12Gy (P=0.02). No statistical association was found in multivariate analysis. A sum of all V18-12Gy of less than 1.5ml was associated with a 14.6% risk of RN, compared with 35.6% when the sum of all V18-12Gy was superior to 1.5ml. The sum of all V18-12Gy larger than 1.5ml was associated with a 74% specificity and 53% sensitivity of RN (P<0.001).
CONCLUSIONS: Based on these results, a small number of BMs show RN during repeated SRT for local or distant recurrent BMs. Local reirradiation was the most predictive factor of brain RN. A V18-12Gy larger than 7.6ml in the case of local reirradiation or larger than 1.5ml in proximity reirradiation were prognostic factors of RN. The more BM patients need radiation therapy, and the longer they survive after irradiation, the higher their individual risk of developing RN.

Metastatic breast cancer is the second most common cause of brain metastasis (BM), and this problem is particularly marked for the amplified HER2 subtype (HER2+), with a cumulative incidence reaching up to 49 % in the ER-/HER2+ subgroup. Literature review shows that therapeutic progress has been major since the marketing of systemic anti-HER2+ treatments, with life expectancies now relatively unaffected by brain development. The recommended treatments are, on the one hand, specific treatment for brain development and, on the other hand, appropriate systemic treatment. Regarding local treatments, we will always favor surgery when possible, especially for large metastases, and stereotaxic radiotherapy, possibly iterative. One should be wary of whole brain irradiation which has never been shown to improve overall survival, but which is clearly associated with more cognitive toxicities. All the systemic anti-HER2 treatments currently on the market have shown efficacy on BM from HER2+ breast cancer and must therefore be chosen above all on the basis of their potential activity on the systemic disease at the time of cerebral evolution. If BM evolution happen without concomitant systemic progression, and local treatment can control it, it is not recommended to change the current medical treatment. Finally, randomized clinical studies opened to patients with active brain disease are starting to be published. The first of them showed the benefit of the triple combination tucatinib-trastuzumab-capecitabine in this context.