Cisplatin and Pemetrexed for lung cancer treatment

Cisplatin + Pemetrexed , non-small cell lung cancer is treated using this two-drug chemotherapy regimen.

Goals of Cisplatin + Pemetrexed treatment

The chemotherapy drugs Cisplatin and Pemetrexed are designed to slow the growth of cancer cells and kill them (the detailed mechanism of action is at the bottom of the article).

Cisplatin + Pemetrexed is given to shrink tumors and reduce the signs and symptoms of lung cancer.

If the disease is not metastatic, meaning lung cancer cells have not spread to other organs, Cisplatin + Pemetrexed is usually given with the aim of completely treating the disease (cure). Two types of administration are used for this purpose:

1. 1. Preventive treatment to eliminate microscopic cells that may remain after lung cancer surgery (adjuvant) treatment;
   2. or treatment before surgery to shrink the tumor, make an operation possible and increase its success (neoadjuvant treatment).

• If metastatic disease is present, Cisplatin + Pemetrexed is given to shrink and control the tumor, prolong survival and reduce the signs and symptoms of lung cancer.

Administration dose and schedule

Recommended starting dose

1. Cisplatin 75 mg/m2 through a vein ( intravenous = İ. V. ), as an infusion lasting more than 1 hour. Given only on day 1, repeated every 21 days.
2. Pemetrexed 500 mg/m2 İ.V. infusion lasting more than 10 minutes. Given only on day 1, repeated every 21 days.

Infusion, means administration through a vein or under the skin. It is a frequently used medical term. For example, fluids are usually administered as a slow infusion through a vein, most often in the arms.

- Approximately 3,5 hours per cycle. Hydration with plain intravenous fluids is usually given before and/or after cisplatin.

Cisplatin + Pemetrexed is generally given in chemotherapy centers to outpatients who then go home.

Cisplatin + Pemetrexed is repeated every 21 days. This is known as 1 cycle. Depending on disease stage, each cycle may be repeated 4-6 times. Treatment duration may vary with the patient's tolerance, treatment response and planned number of cycles; treatment can take 5-6 months.

Side Effects

In a multidrug regimen, each treatment has its own side effects. When given together, clinical study reports provide the best information on drug-related side effects. The side effects of Cisplatin + Pemetrexed according to clinical studies are listed here. Their rates may vary ( for example: % 9-15 ). These studies reported only the numbers of patients experiencing severe and very severe side effects. Mild side effects may therefore be more frequent. 

• Low white blood cell count ( neutropenia ) (%9-15) 
• Hair loss (%12)
• Nausea (%8)
• Weakness (%7)
• Vomiting (%6)
• Low red blood cell count ( anemia ) (%6) 
• Increased bleeding risk (low platelets) (%4)
• Dry skin (%4)
• Reduced kidney function (%3) 
• Constipation (%2)
• Infection (%2)
• Abdominal pain (%2)
• Clotting problem ( thrombosis ) (%2) 
• Fever with low white blood cell counts ( called febrile neutropenia or neutropenic fever ) (%2)

Approximately %7 of patients stop using Cisplatin + Pemetrexed because of unacceptable side effects.

Follow-up

How frequently is follow-up necessary?

Blood tests may be checked before each treatment or between cycles. They usually include a complete blood count ( hemogram ) and biochemistry. Frequently checked biochemical tests include fasting glucose, sodium, potassium, calcium, magnesium, albumin, CRP and creatinine. Your doctor may request other tests according to your clinical condition.

How frequently is imaging needed?

Imaging may be necessary before treatment, at its end and during treatment, or as the doctor decides. Imaging may include X-ray, magnetic resonance imaging (eMaR = MRI), computed tomography (BT) scans or positron emission tomography (PET) scans.

Depending on blood or imaging results, your doctor may recommend continuing cisplatin + pemetrexed, postpone it or change the treatment method.

Points to consider

• Medicines containing ibuprofen or naproxen, non-steroidal anti-inflammatory drugs (NSAİİ), can affect the body's ability to eliminate pemetrexed. NSAİİ drugs should not be used for 2-5 days before treatment and at least 2 days after pemetrexed use.
• Because pemetrexed affects folic acid vitamin metabolism, it causes deficiencies of B12 and folate vitamins. B12 and folate supplementation is therefore given during pemetrexed treatment. The intramuscular injection form of vitamin B12 is preferred; it is recommended one week before the first pemetrexed dose to prevent possible side effects. The injection is generally given every 9 weeks until treatment is complete. 
• Starting 1 week before the first pemetrex dose, folic acid should be taken orally every day ( as a pill by mouth ) to reduce possible side effects. Daily oral folic acid should continue until day 21. after the last pemetrexed dose. 
• Remember to take dexamethasone ( cortisone ) tablets twice daily starting 3 days before pemetrex treatment. This drug helps prevent skin reactions. If you forget to take it, tell your doctor, nurse or pharmacist at the infusion center. An intravenous dose of dexamethasone can be given for the dose forgotten at home. In some cases, the doctor may decide to give intravenous dexamethasone at the infusion center instead of oral dexamethasone at home.
• Cisplatin is a drug with potential to damage the kidneys ( nephrotoxic ). Drinking plenty of water reduces the kidney damage caused by cisplatin.
• A pharmacist must carefully review the medication list and manage interactions or risks appropriately.

Individual drug label information

Cisplatin ( cisplatin, a platinum-group chemotherapy drug )

• Cisplatin is a chemotherapy drug administered by intravenous (I.V.) infusion over approximately 1-2 hours.
• Cumulative toxicity ( total side effects ) from cisplatin in the kidneys can be severe. 
• Other side effects of different cisplatin doses include low blood counts, nausea, vomiting and hearing loss. 
• Dose adjustments may be necessary after poor kidney function and bone marrow suppression (low blood counts).
• Cisplatin is dangerous to the human fetus; pregnancy should be avoided while using this drug.
• It should not be used during breastfeeding because it passes into breast milk.
• Blood levels of cisplatin may decrease in patients treated with anticonvulsant ( antiepileptic ) medicines.
• Caution is necessary in older patients because of kidney problems.
• Nausea and vomiting within 24 hours or within 2-5 days after treatment are expected. Effective anti-nausea medicines can resolve or prevent this problem.
• Diarrhea
• Hearing problems and tinnitus may occur. Children must have hearing tests before treatment and a few years after it ends. 
• Low blood electrolytes: magnesium, potassium, calcium, sodium and phosphate.
• Neuropathy ( nerve damage ). 
• Vision problems generally occur after treatment ends. 
• Liver toxicity generally improves after treatment ends.

Pemetrexed ( trade names Alimta, Pemtrex and Prexet )

• Pemetrexed is administered by intravenous infusion.
• Dose adjustment may be necessary for severe toxicity.
• Painkillers that are non-steroidal anti-inflammatory drugs should not be taken for 2-5 days before treatment or until at least 2 days after pemetrexed use.
• To reduce the risk of pemetrexed side effects, intramuscular vitamin B12 injections and oral folic acid tablets are given. This should begin 7 days before pemetrexed.
• Skin reactions ( allergies ) are common. To reduce them, dexamethasone should be taken orally twice daily starting 3 days before treatment. Alternatively, intravenous dexamethasone can be given on the treatment day.
• Avoid use during pregnancy. If you suspect pregnancy, contact your doctor immediately. Female patients should use contraception ( birth control ) during treatment.

General side effects of Pemetrexed ( Alimta )

• Low red blood cell, white blood cell and platelet counts.
• Reduced liver function and toxicity.
• Nausea, vomiting, diarrhea or decreased appetite and similar gastrointestinal complaints.
• Weakness and lack of strength 
• Constipation 
• Rare allergic reactions 
• Mouth sores

Mechanisms of action

Mechanism of action of cisplatin: Cisplatin's effect on cancer cells is associated with its ability to cross-link purine bases in DNA; it causes DNA damage by interfering with DNA repair mechanisms and subsequently triggers programmed cell death, apoptosis, in cancer cells.

Mechanism of action of pemetrexed: Pemetrexed is a new-generation multitargeted antifolate that inhibits 3 or more enzymes involved in folate metabolism and the synthesis of purines ( adenine and guanine ) and pyrimidines ( cytosine and guanine ). These enzymes are thymidylate synthase, dihydrofolate reductase and glycinamide ribonucleotide formyltransferase. Folates, derivatives of folic acid, are important for cell metabolism and are B vitamin derivatives. They participate in cell division, growth, biosynthesis of amino acids and purine bases, and therefore DNA synthesis.