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Cui et al. Diagnosis and treatment of meningeal carcinomatosis

study in patients with MC from NSCLC concluded that treatment group were higher (64.3% vs. 9.1%, P
adding systemic chemotherapy to combined intra- = 0.012) than gefitinib treatment group in NSCLC
CSF chemotherapy and radiotherapy did not improve with MC. [100] In addition, afatinib is an FDA-approved
the survival time due to insensitivity of the type of second-generation EGFR TKI for NSCLC with
cancer. [93] Data from a retrospective study of 135 EGFR mutations and the effective treatment for CNS
patients showed that the management of systemic metastasis (brain metastasis or MC) in NSCLC who
chemotherapy is closely related to a longer survival had an inadequate response to erlotinib or gefitinib. [101]
time, which is a significant positive prognostic However, there are no reports of the curative effect
factors in patients with MC. [94] However, the choice of of afatinib in patients with MC who failed high-dose
the systemic chemotherapy seems to be based not EGFR TKI. Osimertinib (AZD9291), a third-generation
only on the chemical sensitivity of the primary tumor EGFR TKI, showed effectiveness in an in vivo MC
but also on its ability to pass through the blood-brain- model with a first-and second-generation EGFR TKI
barrier and the effective concentrations of drug in the resistant. [102]
CSF, which can image the chemical characteristics
of the systemic agent. Treatment with high-dose Rearrangement of the ALK gene is observed in
intravenous MTX and cytarabine achieved therapeutic around 4-5% of NSCLC patients. Identifying ALK
CSF levels in patients with hematological malignancy rearrangement is important because patients with
and MC from breast cancer. [22] rearrangement of the ALK gene can be effectively
treated with ALK inhibitors. [103] Crizotinib, a first-
Myelosuppression is the dose-limiting factor of these generation ALK inhibitor, shows poorly BBB
treatment schedules. Moreover, these agents are permeability with a CSF-to-plasma ratio of 0.026, so
toxic and limited by their narrow spectrum of activity the CNS remains a frequent site of recurrence for ALK-
in most solid tumors. positive cases treated with crizotinib. [104,105] Several
case reports showed a higher brain-to-plasma ratio
Molecular targeted therapy of the second-generation ALK inhibitors (ceritinib or
Recently, the application of molecular targeted drugs alectinib) compared to first-generation ALK inhibitors
in the clinic have achieved breakthrough results in and better efficacy against MC for ALK positive
patients with MC who show mutations in the EGFR patients with brain metastases. [106-108] Evidence from
gene or rearrangement of the anaplastic lymphoma studies show that second-generation ALK inhibitors,
kinase (ALK) gene in lung tumor, amplification of especially ceritinib, may be treatment choices in MC
human epidermal growth factor receptor 2 (HER2) patients from ALK-positive NSCLC. [109]
gene in breast cancer, and positivity of CD20 in B
cell lymphoma. Amplification of HER2 is found in about 15-20% of
breast cancer cases.
Mutations in the EGFR gene and rearrangement of
the ALK gene are the two the most frequently studied Trastuzumab is a monoclonal antibody that acts
types of genetic mutations in NSCLC. Identification via the HER2 receptor and is effective for patients
of the mutation status of the EGFR gene is crucial with HER2-positive breast cancer. [110] However, the
because patients harboring EGFR gene mutations effects have been limited due to BBB permeability in
are highly sensitive to EGFR tyrosine kinase inhibitor MC. Stemmler et al. found that the ratio of serum
[79]
(TKI). EGFR mutations are independent positive trastuzumab to CSF trastuzumab in patients with brain
prognostic factors in patients with NSCLC-related metastases from breast cancer was 420:1 before
MC. [95,96] Liao et al. indicated that MC patients radiation, 76:1 after radiotherapy, and 49:1 in cases
[97]
receiving EGFR TKI therapy with an EGFR mutation with accompanied MC after radiotherapy. Trastuzumab
showed longer overall survival compared with those is a highly effective intrathecal chemotherapy agent
without the mutation (10.9 months vs. 2.3 months, that can be used independently, or in combination
P < 0.001). EGFR TKI can pass through the BBB at with other drugs, for the management of MC from
levels of 1-3%. A study demonstrated that high-dose HER2-positive breast cancer. [55,111,112] Several studies
[98]
gefitinib (750 or 1,000 mg daily) improves neurologic revealed that intrathecal trastuzumab can be used
symptoms and achieve therapeutic levels in CSF in safely and efficiently for HER2-postive breast cancer
57% of NSCLC patients with MC who is sensitive to patients with MC with a wide dose range of 4-150 mg. [113]
EGFR TKI. Erlotinib showed higher concentration in Lapatinib, as a dual TKI of HER1 and HER2 is effective
[99]
CSF (28.7 vs. 3.7 ng/mL, P = 0.0008) compared to for HER2-positive breast cancer patients who have
gefitinib. Moreover, a retrospective study indicated progressed while on trastuzumab. [114,115] Nevertheless,
[98]
that the cytologic transformation rates in erlotinib there has been no reported data on lapatinib for
Neuroimmunology and Neuroinflammation ¦ Volume 4 ¦ September 18, 2017 173