With the advent of new technology and therapies, patients with cancer
are living longer. However, improved survival rates bring higher rates of
relapse, particularly central nervous system relapse. The focus of this article
is to review central nervous system complications associated with solid tumors
and lymphoma, current treatment strategies, and a new approach to treatment.
Leptomeningeal malignancy is the seeding of malignant cancer cells to
the leptomeninges. Signs and symptoms usually consist of headache and altered
mental status, including cognitive impairment and confusion. Currently,
leptomeningeal malignancy is diagnosed in about 5% of patients with cancer. The
diagnosis of leptomeningeal malignancy is occurring more frequently and can be
attributed to advances in imaging, improved management of systemic disease and
increased OS. Lymphoma and solid tumor malignancies, including small cell lung
cancer, breast cancer and melanoma, are associated with the highest incidence
of leptomeningeal involvement.
Without treatment, survival of patients with leptomeningeal malignancy
is usually limited to several weeks. Current treatment strategies offer some
improvement in length of survival, upward of 3 to 6 months. Guidelines from the
National Comprehensive Cancer Network stratify patients into one of two risk
groups. Patients deemed poor risk include those with bulky central nervous
system (CNS) disease, extensive neurologic deficits or widely disseminated
disease lacking further treatment options. Those considered good risk include
patients with minimal systemic disease and minor neurologic impairment.
Treatment for leptomeningeal malignancy with patients at poor risk most
often consists of supportive care and palliative measures. Conventional
treatment modalities for the management of patients in the good risk group
include systemic chemotherapy and radiation therapy. Intrathecal chemotherapy
has also become a mainstay in the treatment of leptomeningeal malignancy with
traditional chemotherapy agents, including methotrexate, cytarabine and
thiotepa. Unfortunately, response to these standard therapies remains low.
Poor response to systemic chemotherapy can be explained for several
reasons, the first being the blood-brain barrier. The CNS can act as a safe
haven for tumor cells because of the inability of systemic chemotherapy to
penetrate the barrier. Systemic doses of chemotherapy required to achieve
adequate concentrations at the site of leptomeningeal involvement are
associated with high rates of adverse events, further explaining meager
response. In addition, many of the agents used for systemic chemotherapy are
composed of molecules that are simply too large to pass through the blood-brain
barrier into the CNS. With systemic chemotherapy providing little benefit in
instances of leptomeningeal malignancy, attention has turned to a different
treatment avenue — intrathecal administration.
The use of the monoclonal antibody rituximab (Rituxan; Genentech, Biogen
Idec) has gained favor in the treatment of CD20+ lymphoproliferative
malignancies. IV administration has demonstrated an increase in survival in
patients with systemic disease. Unfortunately, however, this route of
administration has not been shown to decrease the risk for disease occurrence
in the CNS. This outcome is likely related to the inability of rituximab to
adequately cross the blood-brain barrier.
The agent has consistently failed to achieve adequate concentrations in
the cerebrospinal fluid because of poor penetration. It has been demonstrated
that the concentration of rituximab in the cerebrospinal fluid after IV
administration is equal to approximately 0.1% of serum levels. Rituximab’s
mechanism of action, combined with its poor ability to penetrate the
blood-brain barrier, has prompted research into use of this agent for
To date, there have been seven case reports published regarding
intrathecal rituximab use in CNS lymphoma. In these cases, the dose of
rituximab ranged from 10 mg to 40 mg. An initial dose of 10 mg was used most
often and gradually escalated to clinical response or patient tolerance,
whichever occurred first. Of the seven patients, all showed cytologic response,
and four had improvement in symptoms, including resolution of headaches,
seizures and cognitive function.
Of note, one case reported progression of CNS disease. Patient survival
spanned from 4 months to more than 3.5 years. The most common adverse effects
associated with therapy included headache, pain, leg weakness and cramps.
Infusion-related reactions were reported with the 40-mg doses but did not
produce any residual adverse effects.
In 2007, a phase 1 study was published investigating the use of
intrathecal rituximab with goals of defining the agent’s safety, efficacy
and pharmacokinetic profile. The study population included 10 patients, each of
whom was enrolled into one of three rituximab dose cohorts: 10 mg, 25 mg or 50
mg. Doses were administered diluted in normal saline (NaCl 0.9%) or undiluted
as straight drug during a period of 1 minute to 5 minutes.
Each patient received premedication with acetaminophen, diphenhydramine
and cimetidine or famotidine 30 minutes before rituximab administration. Also,
just before rituximab injection, a minimum of 5 mL of cerebrospinal fluid was
removed. Of the eight patients who received 10- or 20-mg doses, none
demonstrated signs or symptoms of major toxicity. Both patients who received
50-mg doses experienced major toxicity, including grade 3 hypertension, chest
pain, tachypnea, diplopia and nausea/vomiting. Resolution of symptoms occurred
within 20 minutes with appropriate supportive care.
Of the 10 patients, six demonstrated cytologic responses; four of those
achieved a complete response. Patient survival ranged from 1.1 weeks to upward
of 134 weeks. Cerebrospinal fluid concentrations 1 hour after dose were 214
mcg/mL and 472 mcg/mL for 10-mg and 25-mg doses, respectively. These
concentrations achieved in the cerebrospinal fluid are similar to those serum
concentrations obtained after systemic rituximab administration.
After the dose, concentrations of rituximab declined rapidly; a
half-life of 34.9 hours was reported for the 25-mg dose. As previously
demonstrated with systemic rituximab therapy, successful response appears to be
correlated with sustained concentrations.
Based on this phase 1 study and the previously mentioned case reports,
intrathecal rituximab shows potential for treatment of leptomeningeal
CD20-associated lymphoproliferative malignancies. Although instances of
toxicity have been described in all cases, most are associated with doses of 40
mg or higher and resolve with appropriate medical management. In all reports,
doses of intrathecal rituximab were delivered via lumber puncture or use of an
With the use of conventional therapies, the prognosis for leptomeningeal
lymphomatosis is dismal. The prime suspect in preventing systemic therapy from
reaching the site of leptomeningeal disease is the blood-brain barrier. To
overcome this barrier, drug administration directly to the site of CNS
involvement is being explored. Existing data suggest that the use of
intrathecal rituximab may be safe and effective. However, more studies are
needed to establish optimal dose, frequency and duration of therapy.
Tiffany Capouch, PharmD, is an oncology pharmacy specialty PGY2
resident at the University of Minnesota Medical Center, Minneapolis.
For more information:
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- Perissinotti AJ. Ann Pharmacother. 2010;44:1633-1640.
- Rubenstein JL. J Clin Oncol. 2007;25:1350-1356.
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