Intrathecal Chemo

Introduction

The lumbar puncture is used either diagnostically, by obtaining CSF, or therapeutically, to administer intrathecal (IT) chemotherapeutic agents. A diagnostic lumbar puncture may be performed during the initial staging or follow-up evaluation of a hematologic or solid malignancy when one suspects CNS involvement. The administration of anti-neoplastic agents into the thecal sac is a method to bypass the blood-brain-barrier and penetrate the CNS, a sanctuary site. Cytotoxic IT chemotherapies are either administered into the lateral ventricle by a surgically placed subcutaneous Ommaya shunt reservoir, or into the lumbar thecal sac by performing a lumbar puncture. Intraventricular administration obviates the need for frequent LPs and provides more uniform drug distribution. However, it carries the risk of surgery and the increased risk of infection, so this decision requires consideration. Use of Ommaya reservoirs is not covered in this review.

Indications

Patients with leptomeningeal metastases (carcinomatous meningitis) have disease in the arachnoid and pia which can invade the leptomeninges and disseminate via CSF into the subarachnoid space or arteries supplying the brain parenchyma. Patients can present with multifocal signs and symptoms, from focal neurologic deficits to signs of meningitis. Unfortunately, the prognosis remains poor, so only the most favorable risk patients should be considered for IT chemotherapy. Additionally, randomized control trials for IT chemotherapy vs supportive care are limited but do not show clear overall survival benefit to IT chemotherapy (1). According to the NCCN, patients with “poor risk” have a Karnofsky Performance Status (KPS) < 60, multiple serious neurologic deficits, encephalopathy, and bulky CNS disease. These patients should be considered for fractionated external beam RT to specific symptomatic sites with palliative care. Those with “good risk” have a KPS >60, no major neurologic deficits or minimal systemic disease with the option of reasonable systemic treatment options. These favorable risk patients should have involved field RT to bulky or symptomatic sites and considered for IT chemotherapy (2). IT chemotherapy has higher efficacy for small tumor deposits or isolated cancer cells. There is limited diffusion of IT chemo into bulky tumors, deposits thicker than 1mm, near nerve root sleeves, and in the Virchow-robin spaces. Ideally, IT chemotherapy should be given to patients with favorable risk, non-bulky leptomeningeal disease with good CSF flow.

CSF Flow Study Prior to Procedure

MRI of the brain and spine with and without gadolinium is the imaging test of choice for suspected focal CNS involvement or leptomeningeal metastases, and should be performed on all patients considered for IT chemotherapy. Signs of obstruction including hydrocephalus should prompt consideration of radiation therapy to that area. Injecting IT chemotherapy into a closed CNS system without can lead to increased drug toxicity without desired diffuse anti-neoplastic efficacy.

About one third of patients with leptomeningeal spread and normal MRI and CT imaging of the brain and spine actually may have abnormal flow (3). Therefore, a CSF flow study should be strongly considered in all patients about to undergo IT chemotherapy. A flow study is usually performed via a intralumbar injection of a radionucleotide ( 111indium) and cisternogram.

Contraindications

The contraindications for lumbar puncture for IT chemo are generally the same as for a diagnostic LP:

  • Plt < 50,000
  • Use of therapeutic anticoagulants (INR > 1.5 or abnormal APTT)
  • Anticoagulation
    • Prophylactic LMWH must be stopped 12 hours before procedure
    • Therapeutic LMWH must be stopped 24 hours before procedure
    • May resume LMWH 24 hours after procedure.
  • Antiplatelet agents:
    • ASA use is not associated with an increased bleeding risk with LP
    • Consider holding for Plavix, but not studied
  • Infection at the site of needle entry
  • Evidence of increased intracranial pressure
  • Evidence of midline shift on imaging

Intrathecal Chemotherapeutic Agents

it-chemo

IT hydrocortisone (15 to 30mg) is sometimes added with IT chemotherapy to theoretically reduce toxicity, however this has not been proven.

Possible complications

Inadvertent introduction of chemotherapy in the subdural or epidural space occurs in up to 10-15% of patients, despite CSF return (1). If you do not remove enough CSF prior to injecting chemo, headache, nausea, vomiting, obtundation, and/or herniation can develop acutely if the total volume of the CSF is increased. Most common complications are those associated with chemotherapy, such as myelosuppression. 20-40% of patients also develop aseptic meningitis which should spontaneously resolve approximately 2-3 days after the procedure. Treatment is based on symptoms and can include steroid therapy.

Procedure Steps

  1. Lumbar Puncture with Ultrasound Localization, see previous pages.
  2. CSF Collection
    • Prior to injecting chemotherapy, the CSF is accessed and sampled. Increases in CSF volume may lead to severe symptoms from headache, nausea and vomiting, or in patients with already increased ICP, herniation. Therefore, an equal amount of CSF must be withdrawn prior to injecting chemotherapy, usually equal to 7-10 mL. After CSF withdrawal and prior to chemotherapy injection, patients may experience a frontal or retro-orbital pressure sensation from decreased CSF volume which resolves rapidly after instillation of chemotherapy.
    • This opportunity should be used to send the fluid for evaluation for malignancy, infection, or bleeding. The following studies should be considered:
      • Protein and glucose and biomarkers (1 mL)
      • Cell count with differential (1 mL)
      • Cytology, flow, and FISH (2 mL, sample must be cellular to be processed)
      • Cancer biomarkers (1 mL)
      • Infectious studies such as cultures, AFB, PCRs, etc. (1-5 mL, depending on tests)
    • Although cytology is the gold standard of diagnosis of leptomeningeal metastases, it is important to note that it can be falsely negative in 10-15% of patients (1). This can also be problematic when using a lumbar puncture to follow clinical disease response to IT chemotherapy. Larger CSF sample volumes and repeat LPs may be considered to reduce the false negative rates.
  3. Injecting Intrathecal Chemotherapy:
    1. Collect an equal amount of CSF as is to be replaced with chemotherapy (see above).
    2. Tap the syringe to remove any air bubbles are in the chemotherapeutic syringe.
    3. Attach the syringe containing the chemotherapy to the hub of the spinal needle.
    4. Gently aspirate a small amount of CSF and check for free flowing CSF. Chemotherapy should not be administered without proper placement, in order to avoid injecting chemo into the subdural, epidural space, or an obstructed subarachnoid space.
      • If there is no CSF flow, remove the syringe. Insert the stylet into the spinal needle and minimally withdraw or advance the spinal needle. Remove the stylet to check for CSF flow.
    5. Slowly inject chemotherapy at a rate of approximately 0.5mL per 1 minute.
    6. Remove the syringe.
    7. Replace the stylet into the spinal needle before withdrawing the needle from the patient.
    8. Apply firm pressure to the needle insertion site, then cover with a dressing for 24 hours.
    9. Discard sharps into the sharps bin and chemotherapeutic syringe into a designated toxic disposal bin.

References

  1. Intrathecal chemotherapy for treatment of leptomeningeal dissemination of metastatic tumours. P, Beauchesne. 2010, Lancet Oncology, Vol. 11, pp. 871-79.
  1. NCCN. NCCN Guidelines Version 1.2016: Central Nervous System Cancers. [Online] 2016. [Cited: August 11, 2016.] https://www.nccn.org/professionals/physician_gls/pdf/cns.pdf.
  1. Diagnosis, management, and survival or patients with leptomeningeal cancer based on cerebrospinal fluid-flow status. . Glantz MJ, Hall WA, Cole BF, et al. 1995, Cancer, Vol. 75, pp. 2919-31.