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METHOTREXATE TREATMENT FOR
LYMPHOMA
James McGowan and Matthew Bridger
CH3
ABSTRACT
New research is being conducted to improve the
patient outcome in cases of primary central
nervous system lymphoma. To date methotrexate
coupled with radiation therapy has become the
most promising treatment regimen.
 Intrathecal methotrexate injections also show
encouraging results as a prophylactic treatment
when full remission is achieved.
 Methotrexate like any other drug has its attributes
and draw backs. We will explain this trade off
using ADAME terms.

INTRODUCTION
Working in medicine, one of the more peculiar
examinations I have performed is intrathecal
(inside the subarachnoid space of the meninges)
administration of Methotrexate.
 I knew that methotrexate is cytotoxic and that
special considerations regarding handling of the
drug were to be taken, beyond this I knew nothing
of what it was used for or why.
 Matt and I would like to share what we have
learned regarding methotrexate and its application
for treating lymphoma with you.

LYMPHOMA PREVALENCE

Of hemopoeitic system cancers, lymphoma is the most common.
Lymphoma ranks as the seventh most prominent cancer in U.S.
adults, and third in pediatric cancers.

Most lymphoma is referred to as either Hodgkin's lymphoma (HL)
or Non-Hodgkin’s lymphoma (NHL).

2009 incidence in the U.S. for all cases of lymphoma are
estimated at 74,500 new cases (8:1 ratio of NHL:HL) with an
estimated death rate of over 20,000 people. The ratio is about
15:1 fatalities NHL:HL. The survival rate is greater for HL than
NHL.

For this presentation we will be referring to treatment and
concerns arising from the more common form of the disease.
HL VS. NHL

While both forms of disease stem from
neoplasia in lymphocytes, they vary in
clinical manifestation, symptoms and
treatment.

Both forms typically are descendant of B
lymphocytes, but T cell lymphoma can
occur.

HL tends to stay localized to a branch of
contiguous lymph nodes and into the
cisterna chyli/thoracic duct. NHL is more
diffuse throughout the lymphatic system

As NHL is more diffuse, it has a much
higher probability of causing malignant
neoplasm throughout the body and into the
central nervous system
PRIMARY CENTRAL NERVOUS SYSTEM
LYMPHOMA

While primary central nervous system lymphoma (PCNSL) is
considered a primary cancer, it originates outside of the CNS
as an activated B lymphocyte that achieved malignancy
across the blood brain barrier (BBB).

B lymphocytes are not able to cross the BBB in healthy
brains; however studies have shown that patients with
HIV/AIDS or on immunosuppressive treatments tend to have
a much higher incidence of PCNSL due to a change in the
BBB’s ability to keep B lymphocytes out of the CNS.

Many patients with PCNSL have presentation of disease in
the eyes either as primary or secondary tumor presenting
unique treatment complications
PCNSL TREATMENTS

Most PCNSLs form in areas that are not operable and
are diffuse throughout tissue without specific mass that
can be removed mechanically. Surgery is usually only
beneficial in obtaining brain biopsies to determine how
infiltrated the deep brain structures have become with
disease.

Chemotherapy and Radiation therapy really are the only
widespread effective treatments at the moment, some
studies have shown progress with biologic treatments
that stimulate the immune system to suppress and
terminate cancerous lymphocytes.
CHOP REGIMEN
Cyclophosphamide-Hydroxydaunorubicin-OncovinPrednisone regimen.
 While this course of treatment may be effective for
peripheral lymphomas, the ability to cross the BBB
and act on cells in the CNS is ineffective with this
traditional form of chemotherapy.
 Addition of this treatment to methotrexate and
radiation therapies have not shown any added
benefit that outweigh the toxic cost of
administering these medications.

RADIATION THERAPY

Most oncologists favor radiotherapy for treatment of PCNSL. Literature
suggests favor of therapy that targets the entire brain and spinal cord, however
if the PCNSL manifests as a mass localized targeting can be performed in
addition to whole brain irradiation.

The law of Bergonie and Tribondeau states: “radiosensitivity of cells is directly
proportional to their reproductive activity and inversely proportional to their
degree of differentiation”

Lymphocytes are the most radiosensitive mature cell in the body. The mature
neuron is very radioresistant as it does not undergo mitosis and it is completely
differentiated from its precursor cell. The dose required to kill lymphocytes is
far less than that which affects neurons.

Radiation therapy works by damaging the DNA of the target cell. Typically it
breaks the deoxyribose-phospate backbone of the helical strand by ionization
of the electrons in the bond between.

The total dose prescribed averages about 4000 rad and as such must be
broken up into fractions so that intracellular recovery of CNS support cells can
occur.
HD-MTX (HIGH DOSE METHOTREXATE)

MTX is introduced intravenously at high doses for treatment
of lymphomas along with radiation therapy as a primary
treatment. It may then be given in a fractionated dose over a
longer time period as a prophylaxis to prevent further tumor
growth.

Intrathecal administration of MTX is useful for preventing
malignant peripheral lymphoma from entering the CNS, while
other treatments are being performed to treat the peripheral
disease.

For ocular lymphomas, MTX can injected directly into the
vitreous humor
NOMOGRAM FOR PATIENT SIZE
MTX DOSAGE

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The previous nomogram is used for dosing calculations
in children. Adult dosing for mg/m2 can be extrapolated
from this to give an accurate idea of the amount of
methotrexate to be administered to an adult patient.
Primary treatment consists of infusions of between 1.5
to 8.0 g/m2 given over a 4 hour period every 11 days for
4 cycles. If resolution of disease is successful then a
prophylactic secondary treatment will follow.
Secondary treatment consists of infusions of between
1.5 to 8.0 g/m2 given over a 4 hour period every 28
days for 11 cycles.
SYNERGISTIC BENEFIT OF MTX AND
RADIOTHERAPY
Research was conducted using MTX as a primary
treatment but it was discovered that when used in
conjunction with radiation therapy the treatment
plans were most effective.
 Formerly non operable tumors are now able to be
treated more effectively using the MTX radiation
combination.
 Radiation breaks the DNA chains and disrupts
nucleotide sequences. MTX disrupts the cells
ability to repair the DNA damage.

TREATMENTS WHEN MTX FAILS

If resolution of disease is unsuccessful after primary MTX
infusions a salvage treatment is initiated.

While salvage treatment varies by oncologists preference
and individual patient parameters.

Typical salvage protocol includes MTX given with mannitol
to increase transmission across BBB as mannitol shrinks
endothelial cells increasing “leakiness” and thus
concentration in CSF.

Salvage therapy also tends to incorporate Rituximab and
Cytarabine as well as many other chemotherapy drugs, but
this discussion is not about them.
LITERATURE REVIEW #1

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High-Dose Methotrexate and Primary Central Nervous System Lymphoma:
Dimaggio and Fahey , 05.22.07
This article focuses on HD-MTX as a primary treatment for PCNSL on an
immunocompetent patient with introcular lesions.
An abstract, backround, case study and conclusion are given
The patient in this study initially received HD-MTX as well as other compounds to
reduce the toxic effects of the MTX that occur in the GI tract and bone marrow. This
patient as developed acute tubular necrosis as a result of MTX damaging her
nephrons.
Resolution of disease occurred after 8 infusions of MTX. Secondary prophylactic
treatments were administered over the course of the next year when disease
recurred.
Primary treatment was resumed with the addition of radiation, but attempts to
clear disease failed and treatment was discontinued after leucopenia developed.
Radiation was continued with some success at alleviation of symptoms, but
disease persisted until discharge to palliative care was initiated.
Article found at http://www.medscape.com/viewarticle/556171
LITERATURE REVIEW 2
This study was very informative on the most up to
date tools for dealing with Primary Central Nervous
System Lymphoma. From now on I will refer to this
class of conditions as PCNSL.
 Two decades ago a three fold rise in patients with
PCNSL was observed. In the past 10 years there
has only been a slight increase. The rate now is
about 0.46 per 100000 patient years in non
immunocompromised patients.
 The rate for immunocompromised patients is
much higher at 0.4 per 1000 patient years. This
100 fold difference is attributed to the patients
immune response.

LITERATURE REVIEW 2 CONTINUED
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This article goes in depth to explain how large B-Cell
lymphoma develops. Typically a normal B lymphocyte is
drawn into the CNS by cellular adhesion molecules “CAMs”.
Epstein Barr material has been identified in over 90% of
PCNSL tissue from immunocompromised patients. Epstein
Barr material is not found on PCNSL tissue from
immunocompetent patients.
The immune system obviously plays a major role in PCNSL
and better understanding of how to treat it will come from
ongoing molecular studies.
The best treatment we have now is Methotrexate injections
coupled with radiotherapy.
Article found at
http://www.medscape.com/viewarticle/550516_6
LITERATURE REVIEW #3
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Intrathecal Methotrexate Reduces Recurrence in Non-Hodgkin's
Lymphoma: Barclay, 08.02.2002
This article is written in support of administering intrathecal MTX
after complete remission of disease has been achieved with
treatments previously listed in this presentation.
The article sites a study where 68 adult patients with complete
remission of PCNSL were observed. Of the 68, 29 patients received
four 8mg/m2 intrathecal injections and 39 did not.
The rates cited for five years recurrence free were 85% for those
receiving the supplementary MTX, and 51% for those not receiving
the drug.
The study concluded that when complete remission is achieved,
prophylactic intrathecal MTX administration greatly increases long
term survival
Article found at http://www.medscape.com/viewarticle/439599
HISTORY
Between 1947 and 1950 Methotrexate was first
synthesized by researchers looking for a drug to
use in the treatment of leukemia.
 In 1956 Methotrexate was found to be the most
effective anti cancer drug in its class from
research involving animal studies.
 In the 1970s Methotrexate was studied for its
effectiveness with various other types of cancer
and other non cancer conditions.
 In 1988 Methotrexate was approved by the FDA as
a treatment for Rheumatoid Arthritis.

PATIENT SELECTION
Anyone who develops Primary Central Nervous
System Lymphoma is a candidate for Methotrexate
based chemotherapy.
 Patients who are 60 years of age or more are not
considered for a combination of Methotrexate and
radiotherapy. It has been found that clinically 90%
of patients 60 years of age or more that receive
the combination mentioned above suffer
neurotoxicity during and after treatment.

EFFECTIVE DOSE/LD50
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We have previously established that the effective dose
for MTX is 1.5 to 8 g/m2 over a 4 hour period. The
frequency that a patient receives a dose depends on a
medication regimen ordered by the oncologist.
The LD50 for intravenous administered MTX in mice is
65-320mg/kg and 15-60mg/kg in dogs
The manner in which MTX is administered to humans
allows treatment to be decreased or discontinued if
adverse effects become to severe.
A specific LD50 for humans was difficult to find and
reports were conflicting.
CNS ANATOMY
CSF FLOW

Ependymal cells line the ventricles of the brain and are covered in cilia that
whip the CSF and get it to circulate throughout the brain. There are
modified layers of ependymal cells that make up the choroid plexus along
the floors of the lateral ventricles, the roof of the third ventricle and inside
the fourth ventricle that serve to secrete CSF.

The typical flow pattern is from the choroid plexus of the ventricles to the
cerebral aqua ducts then either into the center of the spinal cord or into the
cisterns surrounding internal brain structures, to the subarachnoid space
and then eventually outside of the CNS and into venous return by way of
the sinuses in the brain.

MTX concentration in the CSF is a fraction of MTX in plasma when
administered intravenously and the relationship is inverse when
administered intrathecally .
ABSORPTION OF MTX
The MTX is injected into the patient in a slow
infusion through peripheral veins or through a
central venous catheter (CVC).
 The CVC is preferable as the dose is distributed
to the largest volume of blood possible.
 The pathway for MTX to get into the cell follows
that same mechanism for absorbing folate.
 MTX diffuses across the BBB to reach target
cells in the CNS

DISTRIBUTION

The volume of distribution of MTX is about 0.6
L/kg. It is poorly lipid soluble and does not
diffuse across lipid membranes. Its only method
of entering cells is through active transport
processes. It uses the folic acid transport
systems and thus folic and folinic acid may
compete for transport into cells as well as
antagonising the effects inside cells.
ACTION OF METHOTREXATE

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MTX prevents mitosis by
disrupting the cells ability
to synthesize folate
needed during dna
synthesis in S phase.
The drug limits the
production of the active
form of tetrahydrofolate
from the inactive form
dihydrofolate.
Folate is needed for the
de novo synthesis of the
nucleotide thymidine
required for DNA
synthesis.
BIOTRANSFORMATION
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MTX does not get transported into
the CSF and CSF concentrations are
generally < 5% of plasma
concentratons.
Once inside cells MTX is
polyglutamated. The polyglutamation
process inhibits the efflux of
methotrexate from the cells.
Polyglutamated methotrexate may be
retained inside cells for up to 24
hours after serum methotrexate
concentrations fall.
The half life of methotrexate is 8-10
hours. However toxicity may continue
for up to 24 hours after serum
concentrations fall. This is due to the
trapping of polyglutamated
methotrexate inside cells.
COMPARISON OF FOLIC ACID AND MTX
EXCRETION

Methotrexate is primarily processed out of the body by renal
function. MTX is predominantly excreted unchanged in the
urine within 48 hours by both glomerular filtration and active
tubular secretion.

Renal toxicity is more of a function of concentration duration
than actual dose administered.

Aspirin inhibits methotrexate secretion in the proximal tubule
reabsorption thus aspirin may increase toxicity.

folinic acid blocks methotrexate and folinic acid may
accelerate methotrexate excretion.
SIDE EFFECTS/UNDESIRED CYTOTOXICITIES
MTX is administered orally, intravenously, and
intrathecally. The route of administration has
an effect on which part of the body will be
effected.
 Although the amount of MTX administered is
relative to the occurance of side effects, the
duration of the dose is most important.
 Any route of administration will effect the
kidneys as this is where the bulk of MTX is
excreted from the body.

SIDE EFFECTS/UNDESIRED CYTOTOXICITIES
MTX has been linked to causing cardiac
arrhythmia. The findings in a particular case where
this happened showed no signs of structural
disease or cardiac ischemia. Further clinical
investigation is needed to better understand this
rare occurrence.
 MTX disrupts the cell cycle where ever it
concentrates in the body. Places in the body where
cell growth is important are the most susceptible
and produce the most common side effects.

SIDE EFFECTS/UNDESIRED CYTOTOXICITIES
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One of the side effects of HD-MTX is acute tubular
necrosis. Intravenous hydration with sodium bicarbonate
and measurement of urine output and alkalinity can
Organ damage can be minimized by the use of
intravenous calcium leucovorin, a compound that is
similar to folic acid. Calcium leucovorin rescue is
administered 24 hours after the start of the MTX
administration.
All cells that have high mitotic rates will be affected with
GI syndrome occurring 4-10 days after administration.
Bone marrow is also very sensitive, but will tend to take
longer for symptoms to manifest 30-60 days.
SIDE EFFECTS/UNDESIRED CYTOTOXICITIES
The immune system is continually producing
new cells in response to antigens being
presented to it. This can effect various parts of
the body where opportunistic infections my
take hold due to decreased immune response.
 In the pregnant patient MTX can cause
abortion or severe congentital defects.
 Pregnant healthcare workers should avoid
administering MTX

CONCLUSION
MTX is a very effective treatment for people
who have disease that cannot be treated
surgically.
 While the side effects can be undesirable, the
diseases treated with MTX are far worse.
 HD-MTX administered IV, should be coupled
with whole brain radiation to increase chances
of complete remission. Doses of intrathecally
administered MTX should follow to prevent
recurrance.
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WORKS CITED
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Anthony, I, Crawford, D, and Bell, J. “B Lymphocytes in the normal brain: Contrasts with HIV-associated
Infiltrates and Lymphomas”. Brain. 07 Apr 2010. Retrieved from:
http://brain.oxfordjournals.org/cgi/content/full/126/5/1058
Ballentine, Jerry, DO. “Lymphoma” emedicine.com. 07 Apr 2010
Retrieved from http://www.emedicinehealth.com/lymphoma/article_em.htm
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Fahey, Jean, and DiMaggio, Caroline. “High dose Methotrexate and Primary Central Nervous System
Lymphoma”. Journal of Neuroscience Nursing. 07 Apr 2010 . Retrieved from
http://www.medscape.com/viewarticle/556171_2

Ferreri, Andreas, et al. “Questions and answers in the management of primary central
nervous system and ocular lymphomas”. Trends in hematology oncology. 14 Apr 2010.
Retrieved from: http://www.haematologica.org/cgi/reprint/88/9/1063.pdf

Kremer, Joel, MD. “Methotrexate Metabolism and its Relation to Clinical Effects: A Primer”.
Medscape CME. 07 Apr 2010. Retrieved from: http://cme.medscape.com/viewarticle/484254

Lal, Amar, and Masood, Nehal. “Current Approach to Primary Central Nervous System Lymphoma”.
Pakistan Journal of Neuroscience. 07 Apr 2010. Retrieved from:
http://www.pakjns.com/Previous/Archived/Oct-Dec06/Contents/docs/REVIEW_CNS_LYMPH.pdf

Lymphoma: Hodgkin lymphoma part 1. Pathology. University of Virginia School of Medicine. 14 Apr
2010. Retrieved from: http://www.med-ed.virginia.edu/courses/path/innes/wcd/hodgkin.cfm