Meningeal carcinomatosis (MC), also known as meningeal metastases, soft meningeal metastases, or carcinomatous meningitis, is a serious complication involving the central nervous system caused by extensive metastatic infiltration of malignant tumor cells into the soft meninges and subarachnoid space, and its incidence accounts for approximately 3-5% of all tumor patients, ranking third among metastatic complications of the central nervous system. With the prolonged survival of tumor patients and advances in imaging technology, its incidence has been increasing year by year [1]. Although it has been more than 140 years since the first case was reported, the research progress of this disease is very slow. With the wide application of molecular biology detection technology and targeted drugs in clinical practice, the diagnosis and treatment of this disease have made some progress.
1.Diagnosis
At present, the traditional diagnosis of MC mainly relies on clinical manifestations, cerebrospinal fluid cytology and imaging examinations. The symptoms and signs vary with the level of neuronal involvement and thus lack specificity. The clinical symptoms of MC in early stages are complex and sometimes even insidious, so clinicians should raise awareness and consider the occurrence of MC for symptoms such as unexplained increased intracranial pressure, mental abnormalities, and cerebrospinal and neurological involvement [1,2].
1.1 Cerebrospinal fluid cytology
The detection of cancer cells in the cerebrospinal fluid is often considered the gold standard for the diagnosis of MC. However, the positivity rate is low in the early stage of the disease, and although the specificity is high, the sensitivity is poor. It is useful to obtain at least 10.5 ml of cerebrospinal fluid for cytology at the site of neurological damage or abnormalities suggested by MRI to increase the positive rate of cytology tests. Studies have shown that the positive rate of cerebrospinal fluid from the first lumbar puncture is 45%, and the positive rate from the second lumbar puncture can increase to 80%-90%, and more than three lumbar punctures are not beneficial to improve the positive rate of cytology [3]. Even with a desperate search of the cerebrospinal fluid there are still 5% of patients in whom the cerebrospinal fluid examination fails to detect abnormalities, so it is particularly necessary to combine clinical and MRI performance.
Although its specificity is lower than that of cerebrospinal fluid cytology (77% vs. 100%), its sensitivity is almost equal to that of cerebrospinal fluid cytology (76% vs. 77%), and it typically shows direct signs such as meningeal thickening or nodularity, linear or striatal enhancement of the meninges, diffuse enhancement of the meninges, and sometimes caudal signs. It is also associated with secondary changes such as parenchymal volume reduction, cerebral edema, and periventricular edema [4]. It is worth noting that MRI examination has a 10% false-positive rate, so it is not advisable to diagnose MC based on MRI performance alone.
1.3 Biochemical indicators protein levels in cerebrospinal fluid, lactate dehydrogenase, β2-microglobulin, β-glucuronidase, and carcinoembryonic antigen have high sensitivity but lack specificity for MC [5]. Current studies have identified many specific biochemical markers associated with tumor aggressiveness, angiogenesis, and metastasis that would help in earlier diagnosis and treatment of MC patients. A recent study showed that epidermal growth factor receptor (VEGF) has good sensitivity and specificity for detecting malignant tumor cells in the cerebrospinal fluid [6].VEGF is produced by endothelial cell proliferation and tumor angiogenesis, and timely detection of VEGF in patients at high risk for MC such as lung cancer, breast cancer, and malignant melanoma would be beneficial for early treatment of MC patients. Chemokines play an important role in tumor cell metastasis, proliferation and adhesion, for example, chemokine CXCR4 and human stromal cell-derived factor 1 (SDF-1) play an important role in breast cancer cell invasion and metastasis, and they can increase vascular permeability, which leads to easy passage of tumor cells through brain microvascular endothelial cells. In addition the diagnostic value of molecular markers like CXCR1, CXCR2, CXCL-8, and EGFR is under further investigation [6, 7].
At present, the following criteria are mostly used to diagnose MC in China:
① A clear history of cancer;
(ii) clinical signs and symptoms of neurological system that have recently appeared;
③Typical CT and MRI imaging manifestations;
This diagnostic criterion is helpful to improve the accuracy of MC diagnosis, but the sensitivity of cytology and MRI is poor in the early diagnosis of the disease. This diagnostic criterion is useful to improve the diagnostic accuracy of MC.
2. Treatment
At present, the treatment effect of MC is not satisfactory, and there are no unified guidelines for treatment-related toxic side effects. Traditional treatments mainly include surgery, radiotherapy, systemic and intrathecal chemotherapy [1,2,8,9,16]. The treatment goals are mainly to improve or stabilize neurological function, prolong survival time, and improve quality of life.
2.1 Surgical treatment
Neurosurgery gives intracerebroventricular chemotherapy to patients by placing Ommaya capsules, which is safer, more convenient and less painful than the traditional intrathecal administration by lumbar puncture, and intracerebroventricular administration can better distribute chemotherapeutic drugs evenly in the cerebrospinal fluid. A basal concentration of chemotherapeutic agents in the cerebrospinal fluid can be established by increasing the frequency of intrathecal Ommaya administration to achieve an efficacy similar to that of acytosine liposome-like therapy. Recently, Lin et al [10] combined an Ommaya capsule with a ventriculoperitoneal shunt tube to form an integrated chemotherapy-shunt tube, which allows intracerebroventricular chemotherapy to be administered after temporary closure of the shunt tube, thus effectively solving the problem of shunt patients who cannot undergo Ommaya capsule placement. The progression-free survival and overall survival of 24 patients treated with this one-piece tube were 14 weeks and 31 weeks, respectively. Although the incidence of complications after surgical proficiency was low, the risks of the procedure and the infection of the Ommaya capsule should not be ignored.
2.2 Radiotherapy
Radiotherapy is a common treatment for MC, especially for patients with large soft meningeal lesions, because studies have shown that intracerebroventricular chemotherapy can only penetrate the brain parenchyma to a distance of 3 mm outside the ventricular canal, and combined whole-brain local radiotherapy is often essential for MC with a diameter of ≥3 mm. In addition, additional local radiotherapy is often required for cranial nerve and spinal nerve root lesions and for sites identified by radioisotope ventriculography that cause poor CSF flow. The main goals of radiotherapy are to relieve symptoms and pain, shrink the mass, and relieve cerebrospinal fluid circulation disorders [11].Morris et al [12], in a retrospective analysis of 125 patients with non-small cell lung cancer MC, found that although radiotherapy resulted in temporary stabilization of neurological dysfunction, it did not improve the survival time of patients. In addition, whole-brain, whole-spinal cord irradiation is not recommended for MC because of the high mortality and severe myelosuppression that is associated with it [13].
2.3 Chemotherapy
2.3.1 Intrathecal chemotherapy
Intrathecal administration of antitumor drugs is considered a reliable method for the treatment of MC. Direct intrathecal administration of commonly used hydrophilic chemotherapeutic agents can kill subclinical lesions formed by tumor cells deposited in the meninges and tumor cells drifting in the cerebrospinal fluid, preventing the occurrence of further implantation. Local intrathecal chemotherapy has been widely used and has been effective in improving patient survival [14], but its toxic side effects are also common. For example, local intrathecal chemotherapy drugs often cause arachnoiditis, and patients must take oral dexamethasone before intrathecal chemotherapy to prevent arachnoiditis. Routes of administration include trans-Ommaya capsule and lumbar puncture. There are few drugs available for intrathecal chemotherapy, mainly methotrexate (MTX), ara-C and thiotepa, as well as the biological agents IL22, α-IFN and LAK.
2.3.2 Systemic chemotherapy
The main challenge of systemic chemotherapy is how to make more chemotherapeutic drugs cross the blood-brain barrier and blood-cerebrospinal fluid barrier within the tolerable toxicity range of patients. The current empirical treatment confirms that most MC patients can benefit from systemic chemotherapy, mainly because: the blood-brain barrier and blood-cerebrospinal fluid barrier of MC patients are destroyed; systemic chemotherapy can control lesions that are not penetrated by intrathecal chemotherapeutic drugs; and can also benefit patients whose primary lesions are not controlled. There are only a limited number of drugs that can achieve therapeutic concentrations in the cerebrospinal fluid through systemic chemotherapy, mainly BCNU, CCNU, VM-26, FT207 and HD-MTX, and they are often combined with other drugs. In a retrospective study by Oechsle et al [17], systemic chemotherapy was found to be an important factor in the survival time of MC, and its role was even more important than that of local chemotherapy.
2.4 Emerging treatments
Molecularly targeted drugs are widely used in the clinic for their precise efficacy, low side effects and good patient tolerance, which opens up a new idea for the treatment of meningeal metastases. Among them, the epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) class of drugs is the most widely used in the treatment of pulmonary non-small cell lung cancer and has been reported in the MC treatment of non-small cell lung cancer. However, the ability of gefitinib and erlotinib, which are also EGFR-TKI drugs, to penetrate through the cerebrospinal fluid differs greatly, and a recent study found that the ability of erlotinib to penetrate through the cerebrospinal fluid is much higher than that of gefitinib, and therefore erlotinib is strongly recommended for patients to prefer for MC of lung adenocarcinoma origin when their financial ability allows, and erlotinib for patients who have failed gefitinib treatment remain effective [18-20].
Bevacizumab is a recombinant humanized monoclonal antibody that specifically binds to vascular endothelial growth factor (VEGF) to inhibit vascular endothelial bioactivity and reduce neovascularization, thereby inhibiting tumor growth. Currently, bevacizumab has been widely used in the treatment of colorectal cancer, lung cancer, kidney cancer, prostate cancer, ovarian cancer, glioma and other malignant tumors, and new studies have shown that it is effective in the treatment of brain metastases [21], which is especially suitable for MC with intracerebral metastases, and there are reports of the application of bevacizumab for malignant glioma meningeal metastases [22]. Trastuzumab is also a good option for patients with human epidermal growth factor receptor gene (HER-2)-positive breast cancer with meningeal metastases, and it can also be used for Ommaya intracapsular injection [23].
In recent years,the introduction of many new chemotherapeutic agents has given a wide scope for the treatment of MC. Temozolomide is a new oral alkylating agent that can cross the blood-brain barrier and enter the cerebrospinal fluid with low toxic effects, and is more widely used in the treatment of MC. However, the results of a recent phase II clinical trial [24] showed a low efficiency (15.8%) of first-line temozolomide alone in the treatment of MC. There are also case reports of systemic application of letrozole and triamcinolone acetonide chemotherapy for meningeal metastases from breast cancer.