METHOTREXATE TREATMENT FOR LYMPHOMA

CH3

James McGowan and Matthew Bridger

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-Oncovin-Prednisone 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

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

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

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 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

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

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

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

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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