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Page 8 of 20 Pellerino et al. J Cancer Metastasis Treat 2020;6:41 I http://dx.doi.org/10.20517/2394-4722.2020.80

50 CTCs/3 mL (HR = 3.39; 95%CI: 1.01-11.37; P = 0.048). A further analysis revealed that increased values
of ctDNA concentrations (median concentrations of 0.022 ng/µL) were associated with an increased risk
of death (HR = 16.33; 95%CI: 0.69-384; P = 0.08). Overall, they suggested that a significant advantage from
CTCs count and ctDNA analysis in CSF coupled with a simplified MRI assessment, may help to predict
survival. However, only a small number of samples of CSF has been analyzed for CTCs and ctDNA. Thus,
it will be important to validate the prognostic value of MRI assessment and advanced CSF techniques in a
larger and multicenter cohort of LM from NSCLC.

Treatment options for leptomeningeal metastases from NSCLC
Radiotherapy
Different radiation techniques are investigated in BM, such as stereotactic radiosurgery (SRS), whole-
brain radiotherapy (WBRT), intensity modulated radiation therapy (IMRT), or proton beam therapy.
Radiotherapy (RT) does not represent the first line treatment in LM for different reasons. First, a
retrospective analysis has demonstrated a major impact of systemic chemotherapy and targeted agents in
[77]
LM control and OS . Moreover, randomized clinical trials evaluating the efficacy and safety of RT in LM
have not been conducted thus far. Focal RT, such as involved field or SRS, are considered in patients with
local, circumscribed and symptomatic lesions, or in those with CSF flow obstructions due to spinal or
[78]
intracranial blocks in order to improve the distribution of intra-CSF therapy. Wolf et al. retrospectively
analyzed 16 patients with LM from solid tumor (8 NSCLC), treated with SRS, reporting a disease control of
57.1% (partial response in 8 patients) with a median OS of 10 months (6-month and 1-year OS of 60% and
26%, respectively). The Authors suggested that SRS could be added to treat bulky LM in patients also eligible
for systemic therapy, including immuno-therapies and targeted therapies, with the aim to prolong OS.
WBRT may be considered as palliative treatment in patients with symptomatic extensive nodular or linear
LM. Gani et al. reported a median OS of 2 months following WBRT in 27 patients with LM from solid
[79]
[80]
tumors (7 NSCLC). Ozdemir et al. reported a median OS 3.9 months after WBRT in a cohort of 51 LM
from NSCLC, and a longer OS (11.3 months) in patients with ECOG 0-1 and without BM. Brower et al.
[81]
retrospectively analyzed 124 patients with LM from solid tumors (32 NSCLC) and showed a median OS of
9.2 months when WBRT was utilized in conjunction with systemic chemotherapy, with a major benefit in
patients with good KPS (KPS ≤ 50: 1.1 months; KPS 60-80: 2.0 months; KPS 90-100: 5.9 months). Notably,
Ozdemir and Brower identified some prognostic factors (KPS ≥ 90 and absence of BM) in patients with
prolonged OS as compared with historical controls. Craniospinal RT (CSI) is not recommended because
of the poor benefit and the significant risk of developing severe adverse effects (myelotoxicity, enteritis and
[82]
mucositis). Hermann et al. have conducted a retrospective study on 16 patients with LM (5 from NSCLC)
treated with CSI alone (6 patients) or in association with intrathecal methotrexate (10 patients), reporting
a median OS of 2 months after CSI alone, and 4 months after combined treatment. Interestingly, most of
the patients (11/16 - 68%) experienced significant neurologic improvement (improvement in walking in
[83]
7 patients, pain relief in 6 patients, reduction of bladder and bowel incontinence in 3 patients). Devecka et al.
reported OS rates in a cohort of 19 patients with LM (5 from NSCLC); a median OS of 7.3 months, 3.3 months
and 1.5 months for patients with 0, 1 and 2 risk factors according to the proposed prognostic score (KPS
< 70 and the presence of extra-CNS disease), respectively. Recently, Yang et al. have investigated the
[84]
tolerability of proton CSI in 19 patients with LM(11 from NSCLC) in a phase I trial, reporting a median
OS of 8 months (95%CI: 6 to not reached), of whom 4 patients (19%) were disease free ≥ 12 months. Two
patients only reported grade 4 lymphopenia, grade 4 thrombocytopenia, and grade 3 fatigue.

The US National Comprehensive Cancer Network (NCCN) 2020 guidelines for management of LM
recommend focal RT in association with intrathecal chemotherapy in patients with favorable prognostic
factors (KPS ≥ 60, mild neurologic deficits, stable systemic disease, available therapeutic options for
systemic disease). For patients who do not meet these criteria, focal RT to symptomatic lesions or best
[85]
supportive care, are the suggested options [Figure 3]. Lastly, the use of IMRT or proton therapy for
treatment of LM should not be considered as usual therapy.