Treatment of disorder
Carcinomatous meningitis develops several brain nerve disorders, cerebral symptom, and spinal cord and peripheral neurological symptoms, where disseminated cell into intraspinal flows on cerebrospinal fluid circulation, implanted on the central nervous system, then grows at nerve, brain or spinal cord, and advances to parenchyma. Various nerve symptoms are appeared along the neuro axis, and finally with the reason of body position, cells are gathered cisternally near medulla oblongata and grows there then injure medulla to die. Therefore, it is important to diagnose at early as possible, and to perform early stage treatment for better prognosis.
Symptoms are as below.
Diagnosed with enhancing effect of membranous coverings of brain or spinal cord, and cerebrospinal fluid observation (general, cytodiagnosis). Although first cerebrospinal fluid cytology shows negative (positive rate 50%), it is important to try on second (positive rate 80%) and third (100%) times, positive rate is getting high at each time,
Fig.2 is an autopsy example of Carcinomatous meningitis. Blue colored part in tissue is the tumor site of invasion, and this is to destroy tissues along with the infiltration. Although tumor is disappeared by chemotherapy in the cerebrospinal cavity, destroyed tissue remains so that the necessity of early chemotherapy in the cerebrospinal cavity is indicated.
Purpose of the treatment is to release from chronic headache and improve QOL, but it is expected that the early stage discovery may extend the duration of survival. According to the NCC (National Comprehensive Cancer Network) guideline, radiation therapy and chemotherapy in the cerebrospinal cavity are recommended. However, simultaneous radiation chemotherapy is a contraindication issue because it may complicate with leukoencephalopathy. Chemotherapy in the cerebrospinal cavity is the method where Ommaya System (Ommaya reservoir indwelled underneath the skin and indwelled tube in the lateral ventricle are connected) is inserted percutaneously with 25 to 27G butterfly needle and injects MTX, AraC, FdUrd. Normally, MTX 5mg and Cytosine arabinoside （Ara-C） 20mg are co-injected 2 or 3 times a week for 2 weeks duration, and later days once a week as maintenance therapy. Bone-marrow suppression will not appear with this dosage amount and frequency, but in case if they are 3 times a week, bone-marrow suppression may occur. In case when MTX find ineffective but resistance shows up, as shown in Fig.3, writers have clarified that the tolerance property can be overcame with the combination usage of 6- thioguanine.
Regarding to anticancer drug in the cerebrospinal cavity, not all of them can be used but limited to few kinds of drug, such as MTX, cytosine, arabinoside（Ara-C）, thioTEPA, or writer possessed US patented FdUrd. Also, there is cytosine arabinoside sustained preparation DepoCyt of which writer has performed phase I in Japan. This drug keeps effective density for 2 weeks, once cerebrospinal cavity administration is conducted by Lumbar puncture so that it gives less burden to patient, but it has a history of not being authorized by Health, Labor and Welfare Ministry. This DepoCyt can be imported privately.
In late years, for the case of non-small cell lung cancer of EGFR mutant positive in lung cancer, molecular target therapeutics, gefitinib/erlotinib effectiveness is reported. Other than these, below listed several trials are conducting as self-examination sample, and all shows good result.
The method is that artificial spinal fluid is infused continuously from Ommaya reservoir indwelled in brain ventricle, drain them from drainage tube indwelled in lumbar subarachnoid cavity, and administrate MTX and Ara-C at fixed time. With this method, a lot of cancer cells are drained out so that patients say their body became very light. Also, many cases have shown walking becomes possible from bedridden state.
It already writes down in Tumor Cavity Treatment for malignant glioma section, but FdUrd itself has a characteristic to work for only propagation active tissues. And, nerve toxicity by Cerebrospinal Cavity Administration is low, thus we have proven this is an anti-cancer drugs administrative in cerebrospinal cavity so that we have gained US Patent. It is the best anti-cancer drug for carcinomatous meningitis. In clinically, it has less side-effect, shows strong effects.
* Other than the above, as early stage diagnosis, it is proved that the measurement of cerebrospinal fluid Myelin basic protein (ref) and cerebrospinal fluid β- glucuronidase are useful for early diagnosis. (Hidemitsu Nakagawa, et al., Clinical significance of cerebrospinal fluid β-glucuronidase value for intraparenchymal metastatic brain tumor, Adult Disease 36:27-32, 1996)
Nakagawa H,et al.: Measurements of CSF biochemical tumor markers in patients with meningeal carcinomatosis and brain tumors. J Neurooncol 12: 111-120, 1992
Nakagawa H,et al.: Myelin basic protein in the cerebrospinal fluid of patients with brain tumors. Neurosurgery 34: 825-833, 1994