Tokushukai Medical Group

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Cranial Nerve Surgery Disease:Carcinomatous meningitis / Meningioma carcinoma

Symptoms are nerve disorder, headache, Bladder and rectal disorders

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.

  1. Singular or multiple of nerve disorder in 12 brain nerves.Double vision, Peripheral facial nerve paralysis, Diminished hearing/Buzzing, Deglutition disorder are common.
  2. Headache (Meningioma Irritation Symptoms), Motion and sensory impairment of limbs, Fibrous cramps
  3. Bladder and rectal disorders

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.


Treatment goal is the improvement of chronical headache and QOL

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.


Cytarabine sustained preparation can be used by private import.

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.

New trial for Carcinomatous meningitis (Nakagawa, et al)

  1. Method which MTX 1mg small amount is administrated twice a day, morning and evening.
    Gained mitigation of side effect and much better result.
  2. Perfusion chemotherapy in the ventricle and lumbar cerebrospinal cavity with the combined usage of MTX and Ara-C.
    Surg Neurol 45:256-64, 1996

    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.

  3. Sustained MTX Cerebrospinal Cavity Treatment
    The method which MTX is continuously administrated using infusion pump. The method utilized with MTX time-dependent behavior.
  4. MTX and 6-thioguanine combined therapy for MTX resistant meningioma carcinoma disease
    Patients is often to be MTX resistant because drug-resistant mechanisms has already been in active when carcinomatous meningitis is developed. In this case, combination use of 6-thioguanine has proven to be effective to overcome drug resistance.
  5. 5 Fluoro-2’-deoxyuridine (FdUrd)Repetitive cerebrospinal cavity treatment
    US patented: United States Patent-Nakagawa H.Patent Number 6,140311,Date of Patent Oct.31,2000)
    Yamada M, Nakagawa H, et al. J Neurooncol 37: 115-121,
    Nakagawa H, et al. J Neurooncol 45:175-183,1999
    Nakagawa.H, et al. Cancer Chemother Pharmac 43:247-256,1998

    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.

  6. FdUrd continuous cerebrospinal cavity treatment
    Nakagawa H., et al. Neurosurgery 57:266-280, 2005
  7. sodium butyrate continuous cerebrospinal cavity treatment for Cancer meningitis
    95th AACR2004, Orlando; 96th AACR2005, Anaheim, ICACT, 2006, Paris; 43rd ASCO2007, Chicago, ECCO 15/ESMO 34,2009, Berlin;2013AACR Washington DC, 2014AACR, San Diego
    This has shown good results for Cancer meningitis as well as it is effective for malignant glioma.
  8. Phase I of Meningioma carcinoma by Ns-101 (Depo Cyte: Cytarabine sustained preparation)
    Hidemitsu Nakagawa, et al, Cancer and Chemotherapy 34:1799-1805, 2007
    Using cytosine arabinoside sustained preparation, one-time administration to lumber puncture maintains effect for 2 weeks. Nakagawa, et al, and first in Japan, conducts Phase I study and prove its effect and safeness. However, authorization from Health, Labor and welfare Ministry does not approve the drug so that personal importation is only the way.
  9. Y-27362 (Rock inhibitor) combination usage for Meningioma carcinoma Treatment
    Nakagawa H., et al., Mol Cancer Res 3:425-433,2005)Infiltration of cancer cell is controlled; enhanced effect is expected by the combination usage of anti-cancer drug and cerebrospinal cavity treatment.

* 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