Key Terms: Cisplatin, Docetaxel, Folic acid, Malignant pleural mesothelioma, Multitargeted anti-folate, Non-small cell lung cancer, Orphan drug, Vitamin B12.
Definition
Pemetrexed is an anticancer drug that is used to treat malignant pleural mesothelioma and non-small cell lung cancer.
Purpose
Malignant pleural mesothelioma (MPM) is a rare type of cancer of the mesothelium (the lining of the chest cavity around the lungs and the abdomen). About 2,000–2,500 new cases of MPM are diagnosed in the United States annually. Twice that many cases occur in Europe. MPM usually is caused by exposure to asbestos. Inhaled asbestos fibers attach to the outer lining of the lung and the chest wall, causing tumor growth. The disease takes years to develop after asbestos exposure. Symptoms of MPM usually are not apparent or are misdiagnosed until after the disease is well-advanced and difficult to treat with surgery or radiation therapy. Average survival time is 9–13 months after diagnosis. Pemetrexed is used for patients with MPM that cannot be treated surgically.
Lung cancer—usually caused by smoking—is the most common cause of cancer death in the United States. Almost 174,000 people develop lung cancer each year and more than 160,000 die from it annually. Non-small cell lung cancer (NSCLC) accounts for about 80% of all lung cancers and includes squamous cell carcinoma, adenocarcinoma, and large cell carcinoma. Pemetrexed is used to treat stage III or IV NSCLC in patients whose cancer has recurred following chemotherapy and is advancing or has spread (metastasized). Pemetrexed does not improve rates of survival over the standard second-line treatment drug docetaxel but has fewer side effects and thus may improve the quality of life. Neither drug cures recurrent lung cancer.
Description
During the 1980s a new class of drugs called multi-targeted anti-folates (MTA) were developed. These drugs limited the ability of cancer cells to obtain folic acid, a member of the B-vitamin complex that is required for cell growth and reproduction. However, these drugs were considered too toxic to use until pemetrexed was discovered by a Princeton University biochemist in the 1990s.
Pemetrexed disodium heptahydrate (Alimta), manufactured by Eli Lilly, was approved by the U.S. Food and Drug Administration (FDA) in February of 2004 for use in combination with the anticancer drug cisplatin to treat MPM. Pemetrexed, also known as LY231514, was the first drug for treating this type of cancer and, as an orphan drug for a rare disease, received priority review from the FDA. The Orphan Drug Act granted Eli Lilly seven years of exclusive marketing. In August of 2004 the FDA approved pemetrexed for the treatment of NSCLC.
Pemetrexed is a member of a large group of chemotherapy drugs known as antineoplastics or antimetabolites; it sometimes is referred to as an antifolate antineoplastic agent. It inhibits three folate-dependent enzymes that mesothelioma and lung cancer cells need for the synthesis of the nucleotides that make up DNA and RNA. Fast growing cancer cells have a much higher requirement for nucleotides than normal cells.
Effectiveness
The effectiveness of pemetrexed for treating MPM was established in a single clinical trial with 448 patients, comparing combined treatment with pemetrexed and cisplatin to treatment with cisplatin alone. Patients receiving the combined treatment lived three months longer than those receiving cisplatin alone—12 months versus nine months. Patients also had improved lung function. Tumors shrank in 41% of the patients treated with the combined drugs, compared with 17% of those treated with cisplatin alone.
In an earlier clinical trial pemetrexed combined with the chemotherapy drug carboplatin, which is similar to cisplatin, increased the average survival time of mesothelioma patients to 15 months and some patients were still alive after nearly three years. More than twothirds of the treated patients had reduced pain and improvement in other symptoms. Tumors shrank in almost one-third of the patients.
In a clinical trial of 571 patients with recurrent NSCLC, those treated with either pemetrexed or docetaxel had a one-year survival rate of 30%; however, those receiving pemetrexed were significantly less likely to experience the following:
- fever
- infections
- hospitalizations
- hair loss
- numbness in the arms and legs
Recommended Dosage
Pemetrexed is supplied as a sterile powder in single-dose vials of 500 mg pemetrexed and 500 mg mannitol. Pemetrexed is given in a single 10-minute intravenous infusion, once every three weeks. The dose depends on body size and may be adjusted or delayed depending on the patient's blood counts, kidney and liver function, and general condition.
For treating MPM, cisplatin is infused for two hours, beginning about 30 minutes after the end of pemetrexed infusion. As much fluid as possible is taken before and after treatment with cisplatin to keep the kidneys functioning properly. Intravenous fluids usually are given during cisplatin infusion.
Since pemetrexed interferes with both folic acid and vitamin B12, these nutrients are always taken as supplements to prevent severe side effects. Folic acid—350–1000 micrograms—is taken every day for at least five out of seven days prior to pemetrexed treatment. It is continued daily until 21 days after the final treatment. Folic acid is available over-the-counter as well as in many multivitamins. Vitamin B12 is injected during the week before the first pemetrexed treatment and once every nine weeks during treatment.
Patients also take a corticosteroid such as dexamethasone twice a day for three days, beginning the day before pemetrexed infusion, to lower the risk of skin reactions.
Precautions
Pemetrexed causes birth defects if administered to a woman during the conception period or during pregnancy or to a man near the time of conception. Birth control must be used by patients while they receive pemetrexed treatment. Women should not breastfeed while being treated with pemetrexed. Like many other chemotherapy drugs, pemetrexed may cause sterility.
Medical conditions that may interfere with the use of pemetrexed include the following:
- chicken pox or exposure to chicken pox
- gout
- heart disease
- congestive heart failure
- shingles
- kidney stones or kidney disease
- liver disease
- third space fluid (extra body fluid such as ascites in the stomach area or pleural effusion in the lungs and chest)
- other types of cancer
Other precautions during pemetrexed treatment include avoiding the following:
- touching the eyes or inside of the nose without first washing the hands
- cuts or bleeding
- contact sports, bruising, or injury
It is important to avoid vaccinations during and after pemetrexed treatment. It also is important to avoid contact with those who have taken oral polio vaccine within the past several months. A protective face mask that covers the nose and mouth may be used if contact is unavoidable. If possible, people with any infection should be avoided.
Side Effects
Pemetrexed has fewer side effects than many anticancer drugs; however, the most common side effects are as follows:
- anemia (low red blood cell count) that may cause fatigue, paleness, or shortness of breath
- a temporary decline in white blood cells, particularly during the first 10–14 days after each treatment
- a decline in blood platelets
- nausea and vomiting
- diarrhea
- constipation
- loss of appetite
- weight loss
- heartburn
- dry mouth
- redness or sores in the mouth or throat or on the lips a few days after treatment
- rash or itching between treatments
- wrinkled or peeling skin
- burning, tingling, numbness, or pain in the extremities
- muscle aches, cramping, stiffness, or pain
- joint swelling or pain
- difficult or rapid breathing
- pain or burning in the throat
- difficult or painful swallowing
- stuffy or runny nose
- sunken eyes
- irritability
- mood swings or depression
- lightheadedness or dizziness
- confusion
- insomnia
- difficulty concentrating
- hair loss
- increased heart rate
- decreased urination
- severe weakness and fatigue for a few days after treatment
- liver problems, as indicated by fluctuating liver function blood tests
Blood counts are taken before and after each pemetrexed treatment. Rare side effects of pemetrexed include a severe allergic reaction or blood clots.
Pemetrexed suppresses production of blood cells by the bone marrow and decreases the white blood cell count. Symptoms of infection caused by decreased white blood cells include the following:
- fever above 100.5°F (38°C)
- chills
- cough
- hoarseness
- lower back or side pain
- difficult or painful urination
Pemetrexed can reduce blood platelets, thereby increasing the risk of the following:
- unusual bleeding or bruising
- nosebleeds
- bleeding gums when teeth are being cleaned
- black, tarry stools
- tiny red spots on the skin
- blood in the urine or stool
Other serious side effects of pemetrexed can include:
- swollen glands
- increased thirst
- swelling of the eyes, face, fingers, or lower legs
- pain in the chest, groin, or legs, especially in the calves
- sudden severe headaches
- sudden changes in vision
- sudden slurred speech
- fast or irregular breathing
- chest tightness or wheezing
- increased blood pressure
- loss of coordination
- fainting or loss of consciousness
- weight gain
Interactions
Known interactions of pemetrexed with other drugs include:
- oral contraceptives
- vitamins and herbal supplements
- nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin, ibuprofen such as Motrin, naproxen such as Aleve, celecoxib (Celebrex), rofecoxib (Vioxx)
—Margaret Alic, Ph.D.
